Bita3 adrenergic receptor agonists and uses thereof

ABSTRACT

The instant invention provides β 3  adrenergic receptor agonists of structural Formula (I),  
                 
 
     the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, and Y, are as defined herein.  
     The invention further provides intermediates useful in the preparation of the compounds of Formula (I), to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating β 3  adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/242,274 filed Oct. 20, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds of Formula (I)depicted hereinbelow, which compounds are β₃ adrenergic receptoragonists and, accordingly, have utility as, inter alia, hypoglycemic,and anti-obesity agents.

[0003] The invention further relates to intermediates useful in thepreparation of the compounds of Formula (I); to combinations of thecompounds of Formula (I) with anti-obesity agents; to pharmaceuticalcompositions comprising such compounds and combinations; and to methodsof using the compounds, combinations, and pharmaceutical compositions inthe treatment of β₃ adrenergic receptor-mediated diseases, conditions,or disorders in a mammal. The compounds and combinations of theinvention also possess utility for increasing the content of lean meatin edible animals, i.e. ungulate animals such as cattle, swine, and thelike, as well as poultry.

[0004] The compounds and combinations of this invention further possessutility in the treatment of intestinal motility disorders, depression,prostate disease, dyslipidemia, and airway inflammatory disorders.

BACKGROUND OF THE INVENTION

[0005] The disease diabetes mellitus is characterized by metabolicdefects in the production and utilization of carbohydrates which resultin the failure to maintain appropriate blood sugar levels. The resultsof these defects include, inter alia, elevated blood glucose orhyperglycemia. Research in the treatment of diabetes has centered onattempts to normalize fasting and postprandial blood glucose levels.Current treatments include administration of exogenous insulin, oraladministration of drugs and dietary therapies.

[0006] Two major forms of diabetes mellitus are recognized. Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), is the resultof an absolute deficiency of insulin, the hormone that regulatescarbohydrate utilization. Type 2 diabetes, or non-insulin-dependentdiabetes mellitus (NIDDM), often occurs with normal, or even elevated,levels of insulin and appears to be the result of the inability oftissues to respond appropriately to insulin. Most Type 2 diabeticpatients are also obese.

[0007] The compounds of the invention effectively lower blood glucoselevels when administered orally to mammals with hyperglycemia ordiabetes.

[0008] Obesity constitutes a major health risk that leads to mortalityand incidence of Type 2 diabetes mellitus, hypertension, anddyslipidemia. In the United States, more than 50% of the adultpopulation is overweight, and almost 25% of the population is consideredto be obese. The incidence of obesity is increasing in the United Statesat a three-percent cumulative annual growth rate. While the vastmajority of obesity occurs in the United States and Europe, theprevalence of obesity is also increasing in Japan. Furthermore, obesityis a devastating disease which can also wreak havoc on an individual'smental health and self-esteem, which can ultimately affect a person'sability to interact socially with others. Unfortunately, the preciseetiology of obesity is complex and poorly understood, and societalstereotypes and presumptions regarding obesity only tend to exacerbatethe psychological effects of the disease. Because of the impact ofobesity on society in general, much effort has been expended in effortsto treat obesity, however, success in the long-term treatment and/orprevention thereof remains elusive.

[0009] The compounds, pharmaceutical compositions, and combinations ofthe invention also reduce body weight or decrease weight gain whenadministered to a mammal. The ability of the compounds to affect weightgain is due to activation of β₃ adrenergic receptors which stimulate themetabolism of adipose tissue.

[0010] β-Adrenergic agents have been generally classified into β₁, β₂,and β₃ receptor-specific subtypes. Agonists of β-receptors promote theactivation of adenyl cyclase. Activation of β₁ receptors invokes anincrease in heart rate while activation of β₂ receptors induces smoothmuscle tissue relaxation which produces a drop in blood pressure and theonset of skeletal muscle tremors. Activation of β₃ receptors is known tostimulate lipolysis (e.g., the breakdown of adipose tissue triglyceridesinto glycerol and fatty acids) and metabolic rate (energy expenditure),thereby promoting the loss of fat mass. Accordingly, compounds thatstimulate β₃ receptors are therefore useful as anti-obesity agents, andcan be further used to increase the content of lean meat in edibleanimals. In addition, compounds that are β₃ receptor agonists havehypoglycemic activity, however, the precise mechanism of this effect ispresently unknown.

[0011] Until recently, β₃ adrenergic receptors were thought to be foundpredominantly in adipose tissue, however, β₃ receptors are now known tobe located in such diverse tissues as the intestine, (J. Clin. Invest.,91, 344 (1993)) and the brain Eur. J. (Pharm., 219, 193 (1992)).Stimulation of β₃ receptors has also been demonstrated to inducerelaxation of smooth muscle in the colon, trachea, and bronchi. See, forexample, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994),and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of β₃receptors has also been found to induce relaxation ofhistamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp.Ther., 260, 1, 192 (1992).

[0012] The β₃ receptor is also expressed in the human prostate (J. Clin.Invest., 91, 344 (1993). Because stimulation of the β₃ receptor causesrelaxation of smooth muscles that have been shown to express the β₃receptor, i.e. intestinal smooth muscle, one of ordinary skill in theart would also predict relaxation of prostate smooth muscle. Therefore,β₃ agonists are useful in the treatment or prevention of prostatedisease.

[0013] Commonly assigned U.S. Pat. No. 5,977,124 discloses certain β₃adrenergic receptor agonists having utility in the treatment of, interalia, hypoglycemia and obesity.

[0014] U.S. Pat. No. 5,776,983 discloses certain catecholamines usefulas β₃-agonists.

[0015] U.S. Pat. No. 5,030,640 discloses certain α-heterocyclic ethanolamino alkyl indoles, which are useful as growth promoters,bronchodilators, anti-depressants, and anti-obesity agents.

[0016] U.S. Pat. No. 5,019,578 discloses certain α-heterocyclicethanolamines useful as growth promoters.

[0017] U.S. Pat. No. 4,478,849 discloses pharmaceutical compositionscomprising certain ethanolamine derivatives and methods of using suchcompositions in the treatment of obesity and/or hyperglycaemia.

[0018] U.S. Pat. No. 4,358,455 discloses certain heterocyclic compoundsof the structural formula Het—CHOH—CH₂—NH—aralkyl, which compounds areuseful for treating glaucoma and cardiovascular disease.

[0019] European Patent Application Publication No. 0 516 349, publishedDec. 2, 1992, discloses certain 2-hydroxyphenethyl amines which possessanti-obesity, hypoglycemic, and related utilities.

[0020] U.S. Pat. No. 5,153,210 discloses certain heterocyclic compoundsof the formula R^(o)—X—CH(OH)—CH₂—N(R¹)—C(R²)(R³)—(CH₂)_(n)—Y—A—R⁴—R⁵which compounds are useful as anti-obesity and anti-hyperglycaemicagents.

[0021] PCT International Patent Application Publication No. WO 99/65877,published Dec. 23, 1999, discloses heterocyclic compounds having thestructural formula

[0022] which compounds are useful for the treatment of diseasessusceptible to amelioration by administration of an atypicalbeta-adrenoceptor agonist.

SUMMARY OF THE INVENTION

[0023] The instant invention provides β₃ adrenergic receptor agonists ofstructural Formula (I),

[0024] the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, whereinAr, R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X, and Y are as definedhereinbelow.

[0025] In another aspect, the invention provides intermediates useful inthe preparation of the compounds of Formula (I); to combinations of thecompounds of Formula (I), the stereoisomers and prodrugs thereof, andthe pharmaceutically acceptable salts of the compounds, stereoisomersand prodrugs, with anti-obesity agents; to pharmaceutical compositionscomprising the compounds of Formula (I), the stereoisomers and prodrugsthereof, and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, or pharmaceutical compositions comprisingthe compounds of Formula (I), the stereoisomers and prodrugs thereof,and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, and anti-obesity agents; and methods oftreating β₃ adrenergic receptor-mediated diseases, conditions, ordisorders in a mammal which methods comprise administering to the mammalan effective amount of a compound of Formula (I), a stereoisomer orprodrug thereof, or a pharmaceutical composition thereof; or acombination of a compound of Formula (I), a pharmaceutically acceptablesalt of the compound, stereoisomer, or prodrug, and an anti-obesityagent, or a pharmaceutical composition thereof, acceptable salt of thecompound, stereoisomer, or prodrug, and an anti-obesity agent, or apharmaceutical composition thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides β₃ adrenergic receptor agonists ofstructural Formula (I),

[0027] the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of said compounds, stereoisomers and prodrugs, wherein:

[0028] Ar is pyridyl, oxazolyl, thiazolyl, or phenyl;

[0029] R is hydrogen, hydroxy, oxo, halogen, —CF₃, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl, —NR₉R₁₀, —NR₉SO₂R₁₀, —NR₉COR₁₀, or—SO₂R₉;

[0030] R₁ is hydrogen, —(C₁-C₆)alkyl, halogen, —(C₁-C₆)alkoxy, orhydroxy;

[0031] R₂, R₃, R₄ are, independently, hydrogen, or —(C₁-C₆)alkyl;

[0032] R₅ is a 5- or 6-membered ring heterocycle having from 1 to 4heteroatoms selected from the group consisting of oxygen, sulfur, ornitrogen;

[0033] R₆ and R₇ are, independently, hydrogen, halogen, cyano, oxo,—(C₁-C₆)acyl, —CO₂R₉, —NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, —CONR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; —(C₁-C₆)alkyl, optionally substitutedwith —(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy,—(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀,—SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; —(C₃-C₈)cycloalkyl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; aryl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; or heterocycle,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;

[0034] R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and

[0035] R₉ and R₁₀ are, independently, hydrogen, —(C₁-C₆)alkyl,alkylalkoxy, —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy,aryl, or heterocycle;

[0036] X is a direct bond or oxygen; and

[0037] Y is a direct bond, —(C₁-C₆)alkyl, —OCH₂—, —CH₂O—, or oxygen;provided that:

[0038] (i) when Ar is phenyl, R is —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or -SO₂R₉;and

[0039] (ii) when Ar is phenyl, —NR₉SO₂R₁₀, and R₆ and R₇ are bothhydrogen, then R₅ is not imidazolyl.

[0040] The compounds of Formula (I), the stereoisomers and prodrugsthereof, and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, wherein Ar, R, R₁, R₂, R₃, R₄, R₅, R₆, R₇,R₈, X, and Y are as defined hereinabove, that are extant in the(R)-stereo configuration, designated by Formula (I′) hereinbelow, areespecially preferred.

[0041] A first generally preferred subgroup of the compounds of Formula(I), the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, comprisesthose compounds wherein Ar is pyridyl; R, R₁, R₂, R₃, R₄ and R₈, arehydrogen; X is oxygen; Y is a direct bond; and R₅ is a five- orsix-membered ring heterocycle selected from the group consisting ofdihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl,pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl,triazinyl, and triazolyl,

[0042] Among the first generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are particularly preferred:

[0043](R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0044](R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0045](R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0046](R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0047](R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0048](R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0049](R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0050](R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0051](R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0052](R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0053](R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0054](R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;

[0055] (R)-2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0056](R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0057](R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0058](R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0059](R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0060](R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0061](R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0062](R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0063](R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0064](R)-2-{2-[4-(5-methyl-oxazol4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0065](R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0066](R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0067](R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0068](R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0069] (R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol -3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0070](R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0071](R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0072](R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0073](R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0074](R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0075](R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0076](R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0077](R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0078](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0079](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0080](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxyl-ethylamino]-ethanol;

[0081](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxyl]-ethylamino}-ethanol;

[0082](R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol

[0083](R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

[0084](R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0085](R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0086](R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

[0087](R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0088](R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0089](R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl)-phenoxy}-ethylamino)-ethanol;

[0090](R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino-ethanol;and

[0091](R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol.

[0092] Among the first generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are especially preferred:

[0093](R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0094](R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0095](R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0096](R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0097](R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0098](R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0099](R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

[0100](R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;and

[0101](R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol.

[0102] A second generally preferred subgroup of the compounds of Formula(I), the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of said compounds, stereoisomers and prodrugs,comprises those compounds wherein Ar is phenyl; R is —NR₉SO₂R₁₀R₁ ishydrogen, hydroxy, or halogen; R₂, R₃, R₄, and R₈, are hydrogen; X isoxygen and Y is a direct bond; and R₅ is a five- or six-membered ringheterocycle selected from the group consisting of dihydropyridazinonyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl,pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl,triazinyl, and triazolyl.

[0103] Among the second generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are particularly preferred:

[0104](R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0105](R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0106](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0107](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0108](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0109](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0110](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0111](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

[0112](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0113](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0114](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0115](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;and

[0116](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide.

[0117] Among the second generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are especially preferred:

[0118](R)-N-[2-chloro-5-(2-{4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0119](R)-N-[2-chloro-5-(2-{4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0120](R)-N-[2-chloro-5-(1-hydroxy-2-{2-(4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0121](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

[0122](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;and

[0123](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-sulfonamide.

[0124] The instant invention further provides certain amineintermediates useful in the preparation of the compounds of Formula (I)which amine intermediates comprise compounds having the structuralformula

[0125] and the acid addition salts thereof, wherein:

[0126] R₅ is a 5- or 6-membered ring heterocycle selected from the groupconsisting of isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl,oxazolyl, pyrazolyl, pyridazinyl, thiadiazolyl, thiazolinyl, thiazolyl,and triazinyl;

[0127] R₆ and R₇ are, independently, hydrogen, halogen, cyano, oxo,—(C₁-C₆)acyl, —CO₂R₉, —NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, —CONR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; —(C₁-C₆)alkyl, optionally substitutedwith —(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy,—(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀,—SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; —(C₃-C₈)cycloalkyl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; aryl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; or heterocycle,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, -(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;

[0128] R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and

[0129] Y is a direct bond, or —CH₂—.

[0130] Generally preferred amine intermediates of the structural formulashown hereinabove comprise those compounds selected from the groupconsisting of:

[0131] 2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamine;

[0132] 2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0133] 2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0134] 2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0135] 2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0136] 2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0137] 2-[4-(2-ethyl-oxazol-4-yl-4)-phenoxy]-ethylamine;

[0138] 2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy]-ethylamine;

[0139] 2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamine;

[0140] 2-[4-(4-ethyl-thiazol4-yl)-phenoxy]-ethylamine;

[0141] 2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0142] 2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy}-ethylamine;

[0143] 2-[4-(2-isopropyl-thiazol4-yl)-phenoxy]-ethylamine;

[0144] 2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0145] 2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;

[0146] 2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0147] 2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamine;

[0148] 2-(3- methyl-4-oxazol-4-yl)- phenoxy]-ethylamine;

[0149]2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamine;

[0150] 2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine;

[0151] 2-[4-(2-methyl-thiazol-4-yl)-phenoxyl-ethylamine;

[0152] 2-[4-(4-methyl-thiazol-2-yl)-phenoxyl-ethylamine;

[0153] 2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamine;

[0154] 2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamine;

[0155] 2-(4-[1,3,5]oxadiazol-2-yl-phenoxy)-ethylamine;

[0156] 2-(4-oxazol-2-yl-phenoxy)-ethylamine;

[0157] 2-(4-oxazol-4-yl-phenoxy)-ethylamine;

[0158] 2-(4-oxazol-5-yl-phenoxy)-ethylamine;

[0159] 2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0160] 2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine;

[0161] 2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine;

[0162] 2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamine;

[0163] 2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0164] 2-(4-pyrazol-1-yl-phenoxy)-ethylamine;

[0165] 2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamine;

[0166] 2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamine;

[0167] 2-4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamine;

[0168] 2-(4-[1,2,3]thiadiazol-5-yl- phenoxy)-ethylamine;

[0169] 2-(4- thiazol-2- yl-phenoxy)-ethylamine;

[0170] 2-(4-thiazol-4-yl-phenoxy)-ethylamine;

[0171] 2-[4-(2-thiophen-2-ylthiazol-4-yl)-phenoxy]-ethylamine;

[0172] 2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0173] 2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamine;

[0174] 2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamine;

[0175]2-{4-[-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy-ethylamine;

[0176] 2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamine; and

[0177] 2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamine; andthe acid addition salts thereof.

[0178] The compounds and intermediates of the present invention may benamed according to either the IUPAC (International Union for Pure andApplied Chemistry) or CAS (Chemical Abstracts) nomenclature systems.

[0179] The carbon atom content of the various hydrocarbon-containingmoieties may be indicated by a prefix designating the minimum andmaximum number of carbon atoms in the moiety, i.e. the prefix(C_(a)-C_(b)) indicates a moiety of the integer “a” to “b” carbon atoms,inclusive. Thus, for example, (C₁-C₃)alkyl refers to alkyl of one tothree carbon atoms inclusive, or methyl, ethyl, propyl, isopropyl, andall isomeric forms, and straight and branched chain forms thereof.

[0180] The term “alkyl” denotes a straight or branched chainhydrocarbon. Representative examples of alkyl groups comprise methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl,pentyl, and hexyl.

[0181] The term “alkoxy” denotes an alkyl group bonded to an oxygenatom. Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy.

[0182] The term “halogen” or “halo” denotes a radical derived fromchlorine, fluorine, bromine, or iodine.

[0183] The term “cycloalkyl” denotes a cyclic hydrocarbon. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl. It is also possible for the cycloalkylgroup to have one or more double or triple bonds, or a combination ofdouble bonds and triple bonds, but is not aromatic. Examples ofcycloalkyl groups having a double or triple bond include cyclopentenyl,cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like. It is alsonoted that the term cycloalkyl includes polycyclic compounds such asbicyclic or tricyclic compounds.

[0184] The term “acyl” denotes a group derived from an organic acid(—COOH) by removal of of the hydroxy group (—OH).

[0185] The term “aryl” denotes a cyclic, aromatic hydrocarbon. Examplesof aryl groups include phenyl, naphthyl, and biphenyl. The aryl groupcan be substituted or unsubstituted.

[0186] The term “heteroatom” includes oxygen, nitrogen, sulfur, andphosphorus.

[0187] The term “heterocycle”, as employed within the definitions of R₅,R₆, R₇, R₉, and R₁₀, denotes a cyclic, aromatic or non-aromatichydrocarbon radical in which between one and four of the carbon atomstherein have been replaced with heteroatoms. If the heterocyclic radicalcontains more than one heteroatom, the individual heteroatoms may be thesame or different. Representative examples of five- and six-memberedaromatic, or non-aromatic, heterocyclic groups include chromenyl,dihydropyridazinonyl, dihydropyridazinyl, furyl, imidazolidinyl,imidazolyl, indazolyi, indolizinyl, indolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl,naphthyridinyl, oxadiazolyl, oxazinyl, oxazolinyl, oxazolyl,phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazolyl,pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl,pyrrolidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl,thiadiazolyl, thiazolinyl, thiazolyl, thienyl, thiomorpholinyl,triazolyl, and xanthenyl. It is to be understood that the heterocyclicradical may be bonded to another group in more than one way. If noparticular bonding arrangement is specified, then all possiblearrangements are intended. For example, the term “pyridyl” includes 2-,3-, or 4-pyridyl, and the term “thienyl” includes 2-, or 3-thienyl.

[0188] Specific representative examples of five- to six-memberedaromatic, or non-aromatic, heterocyclic groups are 1,4-dioxanyl,3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,1,3,4-dioxazolyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,3-dioxolanyl,1,4-dithianyl, 1,2-dithiolyl, 1,3-dithiolyl, 2-imidazolinyl,2H-imidazolyl, o-isoxazinyl, p-isoxazinyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl,1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl,1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl,5H-1,2,5-oxathiazolyl, 3H-1,2-oxathiolyl, 1,3-oxathiolyl, 2H-pyranyl,4H-pyranyl, 2-pyrazolinyl, 2-pyrrolinyl, 3-pyrrolinyl,1,3,4-thiadiazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, and 1,3,5-trithianyl.

[0189] It is also noted that the heterocyclic radical can comprise morethan one ring. For example, a naphthyl group is a representative of afused bicyclic ring system. It is also intended that the presentinvention include ring groups that have bridging atoms, or ring groupshaving a spiro-orientation. For example, the term “spirocycloalkyl”means a cycloalkyl ring having a spiro union (the union formed by asingle atom which is the only common member of the rings). In addition,it is understood that, unless specifically noted otherwise, all suitableisomers of the cyclic ring groups are included herein.

[0190] Exemplary bicyclic rings consisting of two fused partiallysaturated, fully saturated, or fully unsaturated five- and/orsix-membered rings, taken independently, optionally having one to fourheteroatoms are anthranilyl, benzimidazolyl, benzofuryl,2H-1-benzopyranyl, benzothiazolyl, benzo[b]thienyl, benzo[c]thienyl,2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl,4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl, 4H-1,4-benzoxazinyl,benzoxazolyl, cinnolinyl, cyclopenta[b]pyridinyl, decalinyl, indazolyl,indenyl, indolinyl, indolizinyl, indolyl, 1H-indoxazinyl, isobenzofuryl,isoindenyl, isoindolyl, isoquinolinyl, naphthyl, naphthyridinyl,phthalazinyl, 1,8-pteridinyl, purinyl, pyrano[3,4-b]pyrrolyl,pyrido[3,2-b]-pyridinyl, pyrido[3,4-b]-pyridinyl,pyrido[4,3-b]-pyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, andtetralinyl.

[0191] The term “substituted” means that a hydrogen atom on a moleculehas been replaced with a different atom or molecule. The atom ormolecule replacing the hydrogen atom is denoted as a “substituent.”

[0192] The phrase “therapeutically effective amount” means an amount ofa compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, which amount attenuates, ameliorates, or eliminates one or moresymptoms of a particular disease, condition, or disorder, or prevents ordelays the onset of one or more symptoms of a particular disease,condition, or disorder.

[0193] The term “mammal” means animals including, for example, dogs,cats, cows, sheep, horses, and humans. Preferred mammals include humans,including members of both male and female sexes.

[0194] The phrase “pharmaceutically acceptable” indicates that thesubstance or composition must be compatible chemically and/ortoxicologically, with the other ingredients comprising a formulation,and/or the mammal being treated therewith.

[0195] The terms “treating”, “treat”, or “treatment” embrace bothpreventative, i.e., prophylactic, and palliative treatment.

[0196] In another aspect of the instant invention, the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, can be employed in combination with an anti-obesity agent.

[0197] The anti-obesity agent is preferably selected from the groupconsisting of an apolipoprotein-B secretion/microsomal triglyceridetransfer protein (apo-B/MTP) inhibitor, an MCR-4 agonist, acholecystokinin-A (CCK-A) agonist, a monoamine reuptake inhibitor (suchas sibutramine), a sympathomimetic agent, a serotoninergic agent (suchas fenfluramine or dexfenfluramine), a dopamine agonist (such asbromocriptine), a melanocyte-stimulating hormone receptor analog, acannabinoid receptor antagonist, a melanin concentrating hormoneantagonist, leptin (the OB protein), a leptin analog, a leptin receptoragonist, a galanin antagonist, a lipase inhibitor (such astetrahydrolipstatin, i.e. orlistat), an anorectic agent (such as abombesin agonist), a Neuropeptide-Y antagonist, a thyromimetic agent,dehydroepiandrosterone or an analog thereof, a glucocorticoid receptoragonist or antagonist, an orexin receptor antagonist, a urocortinbinding protein antagonist, a glucagon-like peptide-1 receptor agonist,a ciliary neurotrophic factor (such as Axokine), and humanagouti-related protein (AGRP). Other anti-obesity agents, including thepreferred agents set forth hereinbelow, are well known, or will bereadily apparent in light of the instant disclosure, to one of ordinaryskill in the art.

[0198] Especially preferred anti-obesity agents comprise those compoundsselected from the group consisting of orlistat, sibutramine,fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine,leptin, phenylpropanolamine, and pseudoephedrine.

[0199] Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, phentermine can be prepared as described in U.S. Pat. No.2,408,345; sibutramine can be prepared as described in U.S. Pat. No.4,929,629; fenfluramine and dexfenfluramine can be prepared as describedin U.S. Pat. No. 3,198,834; and bromocriptine can be prepared asdescribed in U.S. Pat. Nos. 3,752,814 and 3,752,888; and orlistat can beprepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917,and 5,643,874.

[0200] The present invention further provides methods of treating β₃adrenergic receptor-mediated diseases, conditions, or disorders in amammal in need of such treatment which methods comprise administering tothe mammal a therapeutically effective amount of a compound of Formula(I), or a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of the compound, stereoisomer, or prodrug; a combinationof a compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the stereoisomer or prodrug and ananti-obesity agent; a pharmaceutical composition comprising an effectiveamount of a compound of Formula (I), a stereoisomer or prodrug thereof,or a pharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent;or a pharmaceutical composition comprising an effective amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent,and an anti-obesity agent.

[0201] Preferably, the β₃ adrenergic receptor-mediated disease,condition, or disorder is selected from the group consisting of obesity,diabetes, irritable bowel syndrome, inflammatory bowel disease,esophagitis, duodenitis, Crohn's Disease, proctitis, asthma, intestinalmotility disorder, ucler, gastritis, hypercholesterolemia,cardiovascular disease, urinary incontinence, depression, prostatedisease, dyslipidemia, and airway inflammatory disorder.

[0202] The invention further provides methods of increasing the leanmeat content in edible animals which methods comprise administering tothe edible animal a lean meat increasing amount of a compound of Formula(I), a stereoisomer, or prodrug thereof, or a pharmaceuticallyacceptable salt of the compound, stereoisomer, or prodrug; apharmaceutical composition comprising a lean meat increasing amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent;or a pharmaceutical composition comprising a lean meat increasing amountof a compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent,and an anti-obesity agent.

[0203] The compounds of Formula (I), the stereoisomers and prodrugsthereof, and the pharmaceutically acceptable salts of the compounds,stereoisomers, and prodrugs, can be administered to a patient at dosagelevels in the range of from about 0.01 to about 1,000 mg per day. For anormal adult human having a body weight of about 70 kg, a dosage in therange of from about 0.01 to about 300 mg is typically sufficient.However, some variability in the general dosage range may be requireddepending upon the age and weight of the subject being treated, theintended route of administration, the particular anti-obesity agentbeing administered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is well within the ability ofone of ordinary skill in the art having the benefit of the instantdisclosure. It is also noted that the compounds of the present inventioncan be used in sustained release, controlled release, and delayedrelease formulations, which forms are also well known to one of ordinaryskill in the art.

[0204] The dosage of the anti-obesity agent will also be generallydependent upon a number of factors including the health of the subjectbeing treated, the extent of treatment desired, the nature and kind ofconcurrent therapy, if any, and the frequency of treatment and thenature of the effect desired. In general, the dosage range of theanti-obesity agent is generally in the range of from about 0.001 toabout 100 mg/kg body weight of the individual per day, preferably fromabout 0.1 to about 10 mg/kg body weight of the individual per day.However, some variability in the general dosage range may also berequired depending upon the age and weight of the subject being treated,the intended route of administration, the particular anti-obesity agentbeing administered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is also well within the abilityof one of ordinary skill in the art having the benefit of the instantdisclosure.

[0205] According to the methods of the invention, a compound of Formula(I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptablesalt of the stereoisomer or prodrug; or a compound of Formula (I), astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug and an anti-obesity agent is administeredto a subject in need of treatment therewith, preferably in the form of apharmaceutical composition. In the combination aspect of the invention,the compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the stereoisomer or prodrug and theanti-obesity agent may be administered either separately or in thepharmaceutical composition comprising both. It is generally preferredthat such administration be oral. However, if the subject being treatedis unable to swallow, or oral administration is otherwise impaired orundesirable, parenteral or transdermal administration will beappropriate.

[0206] According to the methods of the invention, when the compound ofFormula (I), a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of the stereoisomer or prodrug; or a compound of Formula(I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptablesalt of the stereoisomer or prodrug and an anti-obesity agent areadministered together, such administration can be sequential in time orsimultaneous with the simultaneous method being generally preferred. Forsequential administration, the compound of Formula (I), the stereoisomeror prodrug thereof, or the pharmaceutically acceptable salt of thestereoisomer or prodrug and the anti-obesity agent can be administeredin any order. It is generally preferred that such administration beoral. It is especially preferred that such administration be oral andsimultaneous. When the compound of Formula (I), the stereoisomer orprodrug thereof, or the pharmaceutically acceptable salt of thestereoisomer or prodrug, and the anti-obesity agent are administeredsequentially, the administration of each can be by the same or bydifferent methods.

[0207] According to the methods of the invention, the compound ofFormula (I), a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of the stereoisomer or prodrug; or a compound of Formula(I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptablesalt of the stereoisomer or prodrug and an anti-obesity agent ispreferably administered in the form of a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, vehicle, or diluent.Accordingly, the compound of Formula (I), a stereoisomer or prodrugthereof, or a pharmaceutically acceptable salt of the compound,stereoisomer, or prodrug; or a compound of Formula (I), a stereoisomeror prodrug thereof, or a pharmaceutically acceptable salt of thestereoisomer or prodrug and an anti-obesity agent can be administered toa patient separately or together in any conventional oral, rectal,transdermal, parenteral, (for example, intravenous, intramuscular, orsubcutaneous) intracisternal, intravaginal, intraperitoneal,intravesical, local (for example, powder, ointment or drop), or buccal,or nasal, dosage form .

[0208] Compositions suitable for parenteral injection may comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

[0209] These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of microorganismcontamination of the compositions can be accomplished with variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

[0210] Solid dosage forms for oral administration include capsules,tablets, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary pharmaceuticalexcipient (or carrier) such as sodium citrate or dicalcium phosphate or(a) fillers or extenders, as for example, starches, lactose, sucrose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example, paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite;and/or (i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules and tablets, the dosage forms may alsocomprise buffering agents.

[0211] Solid compositions of a similar type may also be used as fillersin soft or hard filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols,and the like.

[0212] Solid dosage forms such as tablets, dragees, capsules, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents, and can also be of such composition that they releasethe active compound or compounds in a delayed manner. Examples ofembedding compositions that can be used are polymeric substances andwaxes. The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

[0213] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosage formmay contain inert diluents commonly used in the art, such as water orother solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

[0214] Besides such inert diluents, the composition can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0215] Suspensions, in addition to the active compound, may furthercomprise suspending agents, as for example, ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth,or mixtures of these substances, and the like.

[0216] Compositions for rectal or vaginal administration preferablycomprise suppositories, which can be prepared by mixing a compound ofthe present invention with suitable non-irritating excipients orcarriers such as cocoa butter, polyethylene glycol or a suppository wax,which are solid at ordinary room temperature, but liquid at bodytemperature, and therefore, melt in the rectum or vaginal cavity therebyreleasing the active component.

[0217] Dosage forms for topical administration of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers, andprodrugs; and the compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs and the anti-obesity agents, maycomprise ointments, powders, sprays and inhalants. The active agent oragents are admixed under sterile condition with a pharmaceuticallyacceptable carrier, and any preservatives, buffers, or propellants thatmay be required. Opthalmic formulations, eye ointments, powders, andsolutions are also intended to be included within the scope of thepresent invention.

[0218] The following paragraphs describe exemplary formulations,dosages, etc. useful for non-human animals. The administration of thecompounds of Formula (I), the stereoisomers and prodrugs thereof, andthe pharmaceutically acceptable salts of the compounds, stereoisomers,and prodrugs; and the compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs and the anti-obesity agents, canbe effected orally or non-orally, for example, by injection.

[0219] An amount of a compound of Formula (I), or a stereoisomer orprodrug thereof, or a pharmaceutically acceptable salt of the compound,stereoisomer, or prodrug; or a compound of Formula (I), a stereoisomeror prodrug thereof, or a pharmaceutically acceptable salt of thecompound, stereoisomer, or prodrug and an anti-obesity agent, isadministered such that an effective dose is received, generally a dailydose which, when administered orally to an animal is usually betweenabout 0.01 and about 1,000 mg/kg of body weight, preferably betweenabout 0.01 and about 300 mg/kg of body weight.

[0220] Conveniently, the compound can be carried in the drinking waterso that a therapeutic dosage of the compound is ingested with the dailywater supply. The compound can be directly metered into drinking water,preferably in the form of a liquid, water-soluble concentrate (such asan aqueous solution of a water-soluble salt).

[0221] Conveniently, the compound can also be added directly to thefeed, as such, or in the form of an animal feed supplement, alsoreferred to as a premix or concentrate. A premix or concentrate of thecompound in a carrier is more commonly employed for the inclusion of theagent in the feed. Suitable carriers are liquid or solid, as desired,such as water, various meals such as alfalfa meal, soybean meal,cottonseed oil meal, linseed oil meal, corncob meal and corn meal,molasses, urea, bone meal, and mineral mixes such as are commonlyemployed in poultry feeds. A particularly effective carrier is therespective animal feed itself; that is, a small portion of such feed.The carrier facilitates uniform distribution of the compound in thefinished feed with which the premix is blended. It is important that thecompound be thoroughly blended into the premix and, subsequently, thefeed. In this respect, the compound may be dispersed or dissolved in asuitable oily vehicle such as soybean oil, corn oil, cottonseed oil, andthe like, or in a volatile organic solvent and then blended with thecarrier. It will be appreciated that the proportions of compound in theconcentrate are capable of wide variation since the amount of activecompound in the finished feed may be adjusted by blending theappropriate proportion of premix with the feed to obtain a desired levelof compound.

[0222] High potency concentrates may be blended by the feed manufacturerwith proteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

[0223] If the supplement is used as a top dressing for the feed, itlikewise helps to ensure uniformity of distribution of the compoundacross the top of the dressed feed.

[0224] Drinking water and feed effective for increasing lean meatdeposition and for improving lean meat to fat ratio are generallyprepared by mixing a compound of the invention with a sufficient amountof animal feed to provide from about 10⁻³ to 500 ppm of the compound inthe feed or water.

[0225] The preferred medicated swine, cattle, sheep and goat feedgenerally contain from 1 to 400 grams of active ingredient per ton offeed, the optimum amount for these animals usually being about 50 to 300grams per ton of feed.

[0226] The preferred poultry and domestic pet feeds usually containabout 1 to 400 grams and preferably 10 to 400 grams of active ingredientper ton of feed.

[0227] For parenteral administration in animals, the compounds of thepresent invention may be prepared in the form of a paste or a pellet andadministered as an implant, usually under the skin of the head or ear ofthe animal in which increase in lean meat deposition and improvement inlean mean to fat ratio is sought.

[0228] In general, parenteral administration involves injection of asufficient amount of a compound of the present invention to provide theanimal with 0.01 to 20 mg/kg/day of body weight of the activeingredient. The preferred dosage for poultry, swine, cattle, sheep,goats and domestic pets is in the range of from 0.05 to 10 mg/kg/day ofbody weight of active ingredient.

[0229] Paste formulations can be prepared by dispersing the activecompound in a pharmaceutically acceptable oil such as peanut oil, sesameoil, corn oil or the like.

[0230] Pellets containing an effective amount of a compound,pharmaceutical composition, or combination of the present invention canbe prepared by admixing a compound of the present invention with adiluent such as carbowax, carnuba wax, and the like, and a lubricant,such as magnesium or calcium stearate, can be added to improve thepelleting process.

[0231] It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, it has been found that implants mayalso be made periodically during the animal treatment period in order tomaintain the proper drug level in the animal's body.

[0232] The present invention has several advantageous veterinaryfeatures. For the pet owner or veterinarian who wishes to increaseleanness and/or trim unwanted fat from pet animals, the instantinvention provides the means by which this may be accomplished. Forpoultry and swine breeders, utilization of the method of the presentinvention yields leaner animals which command higher sale prices fromthe meat industry.

[0233] The terms pharmaceutically acceptable salts, esters, amides, orprodrugs mean the carboxylate salts, amino acid addition salts, esters,amides, and prodrugs of a compound that are, within the scope of soundmedical judgment, suitable for use with patients without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible.

[0234] The term “salts” refers to inorganic and organic salts of acompound of Formula (I), or a stereoisomer, or prodrug thereof. Thesesalts can be prepared in situ during the final isolation andpurification of a compound, or by separately reacting a compound Formula(I), or a stereoisomer or prodrug thereof with a suitable organic orinorganic acid and isolating the salt thus formed. Representative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, besylate, palmitiate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, for example, Berge, et al., J. Pharm. Sci., 66, 1-19(1977).

[0235] The term “prodrug” means a compound that is transformed in vivoto yield a compound of Formula (I), a stereoisomer thereof, or apharmaceutically acceptable salt of the compound or stereoisomer. Thetransformation may occur by various mechanisms, such as throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

[0236] For example, if a compound of Formula (I), a stereoisomerthereof, or a pharmaceutically acceptable salt of the compound orstereoisomer, contains a carboxylic acid functional group, a prodrug cancomprise an ester formed by the replacement of the hydrogen atom of theacid group with a group such as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0237] Similarly, if a compound of Formula (I), or a stereoisomerthereof, comprises an alcohol functional group, a prodrug can be formedby the replacement of the hydrogen atom of the alcohol group with agroup such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0238] If a compound of Formula (I), or a stereoisomer thereof,incorporates an amine functional group, a prodrug can be formed by thereplacement of a hydrogen atom in the amine group with a group such asR-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl isa natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ whereinY₀ is (C₁-C₄) alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N- or di-N,N-(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0239] The compounds of Formula (I) may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of Formula (I)as well as mixtures thereof, including racemic mixtures, form part ofthe present invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of Formula(I) incorporates a double bond, both the cis- and trans- forms, as wellas mixtures, are embraced within the scope of the invention.

[0240] Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. Also, some of the compounds of Formula (I) may beatropisomers (e.g., substituted biaryls) and are considered as part ofthis invention.

[0241] The compounds of Formula (I) may exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like, and it is intended that the invention embraceboth solvated and unsolvated forms.

[0242] It is also possible that the compounds of Formula (I) may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. For example, all of the tautomeric forms ofthe imidazole moiety are included in the invention. Also, for example,all keto-enol or imine-enamine forms of the compounds are included inthe invention.

[0243] It is also intended that the invention disclosed herein encompasscompounds of Formula (I) that may be synthesized in vitro usinglaboratory techniques, such as those well known to the synthetic organicchemist of ordinary skill, or synthesized using in vivo techniques, suchas through metabolism, fermentation, digestion, and the like. It is alsointended that the compounds of Formula (I) may be synthesized using acombination of in vitro and in vivo techniques.

[0244] The present invention also embraces isotopically-labelledcompounds of Formula (I), which are identical to those recited herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. The compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, or prodrugs which contain the aforementionedisotopes and/or other isotopes of other atoms are intended to be withinthe scope of this invention.

[0245] Certain isotopically-labelled compounds of Formula (I), forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in compound and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by carrying out the procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an isotopically labelled reagent for a non-isotopicallylabelled reagent.

[0246] The compounds of Formula (I) may be prepared by processes whichinclude those known, or those analogous to those known, in the chemicalarts. Such processes for the preparation of the compounds of Formula (I)as defined hereinabove are illustrated according to the exemplarysynthetic sequences set forth hereinbelow in Schemes I through Ill.Furthermore, Schemes IV through VI illustrate exemplary synthetic routesto the intermediates useful in the production of the compounds ofFormula (I). Unless otherwise qualified, the meanings of the genericradicals are as indicated hereinabove.

[0247] In the synthetic sequence designated Scheme I, an appropriatelysubstituted oxirane derivative (III) is condensed with an appropriatelysubstituted amine (II) to produce a compound of Formula (I).

[0248] The amine derivatives (II) may be conveniently prepared asdepicted in general Schemes IV, V, and VI hereinbelow, however, othermethods of preparing such amine derivatives will be known to one ofordinary skill in the art having benefit of the teachings of the instantdisclosure.

[0249] The oxirane derivatives (III) may be prepared according to knownmethods, including those set forth in, for example, U.S. Pat. Nos.5,541,197, 5,561,142, 5,705,515, and 6,037,362, the disclosures of whichare all incorporated herein by reference. Where available, such oxiranederivates may also be obtained from commercial sources.

[0250] The condensation of oxirane (III) and amine (II) is mostconveniently performed at an elevated temperature in a polar, proticsolvent, for example, an alcohol such as methanol or ethanol.Alternatively, a co-solvent system may also be employed, for example, byadding a polar, aprotic co-solvent such as dimethylsulfoxide to theprotic solvent. Isolation and purification of the compound of Formula(I) thus formed may then be effected according to known methods. Anexample of such condensation and purification is disclosed hereinbelowin the general preparative method denoted Method A.

[0251] Alternatively, as depicted in Scheme II, the compounds of Formula(I) may also be prepared by condensing an appropriately substitutedprotected alcohol (IV) with an amine (II). The protected alcohol (IV)incorporates a suitable leaving group that is susceptible todisplacement by nucleophilic attack of the nitrogen atom of amine (II).Suitable leaving groups that may be employed in protected alcohol (IV)may comprise, for example, mesylates, tosylates, and nosylates, orhalides, for example, chlorides, bromides, or iodides. The protectedalcohol derivatives (IV) may be prepared according to known methods,including, for example, those methods disclosed in commonly-assignedU.S. Pat. No. 6,008,361, the disclosure of which is hereby incorporatedby reference. However, other methods of preparing such protectedalcohols will be known, or apparent in light of the instant disclosure,to one of ordinary skill in the art. See, for example, T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,(1991), and the references cited therein.

[0252] The condensation of protected alcohol (IV) and amine (II) istypically effected in the presence of an appropriate,sterically-hindered base, for example, N,N-diisopropylethylamine(Hunig's Base) in a polar, aprotic solvent, such as dimethylsulfoxide,at elevated termperature. The protected amino alcohol (V) thus formedmay then be deprotected according to well-known preparative methods, forexample, where (V) is a silylated derivative, preferably by treatmentwith tetrabutylammonium fluoride. An example of such condensation anddeprotection is disclosed hereinbelow in the general preparative methoddenoted as Method B.

[0253] Alternatively, as shown in Scheme III, the compounds of Formula(I) may also be prepared by dehalogenation of a compound of Formula(Ia), wherein the Ar group represents an appropriately substituted6-chloropyridine derivative.

[0254] The dehalogenation of the above-mentioned 6-chloropyridinederivative (Ia) may be effected according to known methods. Mostconveniently, such dehalogenation is performed using a metal catalyst,preferably palladium on carbon, in a polar solvent, such as methanol.The reaction is preferably conducted at room temperature over a periodof several hours, i.e. overnight. Other methods of effectingdehalogenation reactions of this kind will be known to one of ordinaryskill in the art. An example of such dehalogenation reaction isdisclosed hereinbelow in the general preparative method denoted MethodC.

[0255] With reference to Schemes I and lI, the aforementioned aminederivatives of formula (II) may be prepared according to the exemplarysynthetic sequences depicted hereinbelow in Schemes IV, V, and VI. It isto be understood, however, that such examples are offered for purposesof illustration of these embodiments of the instant invention and arenot to be construed in any manner as limitations thereof, as othermethods of preparing such amine derivatives will be known, or apparent,to one of ordinary skill in the art having benefit of the instantdisclosure.

[0256] General Scheme IV hereinabove depicts a convenient, exemplarysynthetic route to amine derivatives (II) in which an appropriatelysubstituted anisole derivative (VI) serves as the synthetic platformupon which the heterocyclic moiety R₅ may be constructed. Such anisolederivatives will be well known to one of ordinary skill in the art andmay either be prepared according to known methods or obtainedcommercially. The anisole derivatives (VI) may be functionalized asillustrated hereinbelow in Schemes IVa to IVc to produce heteroarylderivatives (VII). Although general Scheme IV, and the synthetic schemesrelated thereto that are shown below, depict the use of an anisolederivative (VI), it is to be understood that an appropriatelysubstituted phenol derivative may also be employed in place of theanisole derivative, where such phenol is chemically compatible withother functional groups and/or reagents that may be present or utilizedin subsequent synthetic steps. The heteroaryl derivatives (VIII) soproduced are then demethylated, for example, with methanesulfonic acidor boron tribromide, to form an appropriately substituted phenolderivative (VIII). The phenol derivative (VIII) so produced is thencoupled with a protected amino alcohol to form the amine-protectedderivative (IX). An example of such coupling reaction is providedhereinbelow in Example 1. The ability to select an appropriateamine-protecting group to form the amine-protected alcohol (IX) is wellwithin the purview of one of ordinary skill in the art. For examples oftypical amine protecting groups, see, for example, T. W. Greene, supra,and the references cited therein. The coupling reaction between thephenol derivative (VIII) and the amine-protected derivative (IX) may beeffected according to methodologies that will be well-known to one ofordinary skill in the art, however, such coupling is preferably effectedvia a so-called Mitsunobu reaction. This reaction is typically performedwith stirring at room temperature (or at elevated temperature ifrequired) in the presence of a dehydrating agent, for example, astoichiometric amount of a diazocarboxyl compound, such as1,1′-(azodicarbonyl)-dipiperidine (ADDP), and a phosphine, for example,triphenylphosphine. The reaction can be carried out in anyreaction-inert solvent such as tetrahydrofuran, dimethylformamide, or ahydrocarbon, or halogenated hydrocarbon solvent. The amine-protectedderivative (IX) so formed is then deprotected in a conventional manner,for example, by treatment with methanesulfonic acid, or various otherdeprotecting agents under conditions that will be well known to one ofordinary skill in the art, including hydrogenoloysis in the presence ofa suitable metal catalyst, such as palladium on carbon in an inertsolvent. The hydrogenolysis reaction is typically effected anywhere fromroom temperature up to about 90° C. An example of such a deprotectionreaction is provided hereinbelow in Example 2.

[0257] The following specific schemes, designated Schemes IVa to IVe,exemplify the syntheses of various synthetic precursors to the variousamine derivatives (II) depicted in Schemes I, II, and IV wherein theheterocyclic moiety R₅ is as shown hereinbelow. As before, it is to beunderstood that these examples are offered for purposes of illustration,and not of limitation.

[0258] The thiazole, oxazole, and imidazole-functionalized anisolederivatives (VIIa) may be produced according to the exemplary routedepicted in Scheme IVa, beginning with an appropriately substitutedthioamide, amide, or amidine derivative (VIa). Such thioamide, amide, oramidine derivatives will be well known to one of ordinary skill in theart and may either be obtained commercially or prepared by knownpreparative methods. The thioamide, amide, or amidine derivative (VIa)is cyclized with an appropriate α-bromoketone to form the desiredderivative (VIIa). Such α-bromoketones will also be well known to oneskilled in the art and may also be obtained commercially or prepared byone of ordinary skill in the art according to known methods.

[0259] Alternatively, regioisomeric thiazole, oxazole, and imidazolederivatives (VIIb) can be synthesized according to the exemplarysynthetic route shown in Scheme IVb. In Scheme IVb, an appropriatelysubstituted acylated anisole derivative (VIb) is α-halogenated,preferably α-brominated, according to conventional methods, for example,by the reaction of (VIb) with tetrabutylammonium tribromide (TBABBr₃),or dibromobarbituric acid (DBBA). The substituted α-bromoketone (VIb′)so produced is then condensed with an appropriate thioamide, amide, oramidine derivative to form the thiazole, oxazole, or imidazolederivative (VIIb). Such condensation may be effected neat, or,preferably, in the presence of a polar solvent, such as an alcohol, or ahalogenated hydrocarbon, such as chloroform.

[0260] The intermediate isoxazole or pyrazole derivatives (VIIc) may besynthesized according to the exemplary route depicted in Scheme IVc. InScheme IVc, an acylated anisole derivative (VIc) is reacted with anappropriately substituted ester and a crown ether, for example,18-crown-6, in the presence of an organic base, such as potassiumtert-butoxide, in a non-protic solvent, such as tetrahydrofuran, atelevated temperature. The diketo derivative (VIc′) thus formed is thencyclized with an appropriately substituted hydrazine derivative orhydroxylamine in a polar solvent, such as ethanol, at elevatedtemperature to produce pyrazole derivative (VIIc), and the regioisomerthereof (VIIc′).

[0261] The intermediate isoxazole or pyrazole derivatives (VIId) may besynthesized according to the exemplary route depicted in Scheme IVd. InScheme IVd, an appropriately substituted diketo derivative (IVd) iscondensed with an appropriately substituted hydrazine derivative orhydroxylamine to furnish phenol derivatives (VIId). The intermediatediketo derivative (VId) may be obtained from commercial sources orprepared according to known methods. The condensation reaction ispreferably effected in a polar solvent, such as ethanol, at elevatedtemperature. An exemplary preparation of a compound of formula (VIIId)is provided in Example 35 hereinbelow.

[0262] The intermediate imidazole derivatives (VIIe) or pyrazolederivatives (VIIe′) may be prepared as outlined hereinabove in exemplaryScheme (IVe). As depicted in Scheme (IVe), an appropriately substitutedboronic acid derivative (VIe) is reacted with an appropriatelysubstituted imidazole or pyrazole derivative in the presence of asuitable catalyst, preferably copper (II) acetate, in a halogenatedhydrocarbon solvent, preferably dichloromethane, to form imidazolederivative (VIIe) or pyrazole derivative (VIIe′) respectively. Theboronic acid derivatives (VIe), as well as the appropriately substitutedimidazole or pyrazole derivatives, may be either obtained commerciallyor prepared according to known methods. An exemplary preparation of acompound of formula (VIIe′) is provided in Example 30 hereinbelow.

[0263] Scheme V hereinabove depicts an exemplary, alternative route to aformula (II) amine beginning with an appropriately substitutedfluorobenzene derivative (X). Such fluorobenzene derivatives (X) may beobtained commercially, or, in the alternative, may be prepared by knownmethods. The fluorobenzene derivative (X), which serves as a syntheticscaffold from which the heterocyclic moiety R₅ is assembled, is reactedwith an appropriately functionalized amino alcohol to furnish amine(II). The reaction between the amino alcohol and the fluorobenzenederivative (XI) is typically effected in a polar, aprotic solvent,preferably dimethylsulfoxide, at an elevated temperature in the presenceof an organic or inorganic base, preferably potassium tert-butoxide. Arepresentative synthesis of an amine (II) as depicted in Scheme V isprovided hereinbelow in Examples 28 and 29.

[0264] Scheme Va above illustrates a convenient, generally applicablesynthetic approach to the heterocyclic amine precursor of formula (XI)shown in Scheme V, wherein R₅ represents a pyridazin-3-one moiety. Here,the fluorobenzene starting material (Xa) is condensed with hydrazinehydrate in a polar, protic solvent, such as ethanol, at elevatedtemperature, to form amine precursor (XIa). An exemplary synthesis ofprecursor (XIa) as shown in Scheme Va is disclosed hereinbelow inExample 28.

[0265] A generally applicable, alternative synthesis of an amineintermediate (II) is shown in Scheme VI beginning with protected amine(XII). The protected amine (XII), which may be prepared by knownmethods, is functionalized so as to form amine (IX) which subsequentlyserves as a synthetic basis for the preparation of protected amine (IX)which incorporates the substituted heterocyclic moiety R₅.Representative preparations of such heterocyclic moieties areillustrated hereinbelow in Schemes VIa to VId. Typically, the protectedamine starting material (XII), wherein X is a direct bond, is preparedby appropriate derivatization of a commercially available phenalkylaminestarting material. An example of such derivatization is disclosedhereinbelow in Example 11. Where X represents oxygen, such protectedamine derivatives (XII) are typically derived from an aforementionedMitsunobu coupling reaction between an appropriately substituted,commercially available phenol and an ethanolamine derivative. An exampleof such a coupling reaction is provided hereinbelow in Example 20.

[0266] In Scheme VIa, the amine-protected derivative (XIIa) is acylatedunder standard Friedel-Crafts reaction conditions to form the acylderivative (XIIa′). Such acylation will be well known to one of ordinaryskill in the art and is typically effected by treating (XIIa) with anappropriately substituted acyl chloride in the presence of a Lewis acid,i.e. aluminum (III) chloride in a reaction-inert solvent, such asdichloromethane or similar halogenated hydrocarbon solvent at, or below,room temperature. The acylated derivate (XIIa) so produced is thenα-halogenated relative to the keto group of the acyl moiety to formα-haloketone (XIIa″). Such α-halogenation, preferably α-bromination, maybe effected according to conventional methods, preferably by thereaction of (XIIa) with tetrabutylammonium tribromide (TBABBr₃), ordibromobarbituric acid (DBBA). An example of such an α-brominationreaction is provided hereinbelow in Example 21. The preferredα-bromoketone (XIIa″) so produced is then condensed with an appropriatethioamide, amide, or amidine derivative to form a protected thiazole,oxazole, or imidazole derivative (IXa) respectively. Although thecondensation reaction may be effected in the absence of a solvent, i.e.neat, for purposes of product purity and ease in reaction work-up andpurification, it is generally preferred that the condensation reactionbe performed in a reaction-inert solvent, including, for example,ethanol, chloroform, or similar solvent. An example of such condensationreaction is provided in Example 22 hereinbelow. The protected aminederivative (IXa) so produced may then be deprotected according to themethodologies described hereinabove in Scheme IV. An example of suchdeprotection reaction is provided hereinbelow in Example 23.

[0267] The protected triazole derivatives (IXb) shown in Scheme VIb maybe produced by reaction of an amine-protected amide derivative (XIIb)with an appropriately substituted dimethylaminodimethylacetal atelevated temperature under neat conditions followed by treatment withhydrazine hydrate in glacial acetic acid, also at elevated temperature.The protected amine derivative (IXb) thus formed may then be deprotectedas shown and described hereinabove in Scheme IV.

[0268] The oxadiazole derivatives (IXc) shown in Scheme VIc may besynthesized by reacting an appropriately substituted hydrazide (XIIc)with an acyl chloride under standard conditions, i.e., in the presenceof a base, preferably an organic base such as triethylamine, in areaction-inert solvent such as dichloromethane. If necessary, theresulting diacyl hydrazide intermediate may then be treated with acyclizing agent, such as triflic anhydride, to effect ring closure. Theprotected amine derivative (IXc) thus produced may then be deprotectedas shown and described hereinabove in Scheme IV. An exemplary syntheticsequence, which illustrates the preparation of a protected aminederivative (IXc), as well as the subsequent deprotection thereof, isprovided in Examples 24 to 27 hereinbelow, wherein Y represents —CH₂—.

[0269] The protected thiazole, oxazole, or imidazole derivates (IXd)depicted in Scheme VId may be prepared beginning with nitrile (XIId).Typically, nitrile (XIId) is prepared via the aforementioned Mitsunobucoupling reaction between commercially available phenol and ethanolaminederivatives. Reduction of nitrile (XIId) with, for example, a metalhydride such as diisobutylaluminum hydride (DIBAL-H) in areaction-inert, hydrocarbon solvent such as toluene or hexanes, or ahalogenated hydrocarbon solvent such as dichloromethane furnishesaldehyde (XIId′). The aldehyde (XIId′) so produced is then α-halogenatedto form α-haloaldehyde (XIId″). Such α-halogenation is preferablyeffected as set forth hereinabove in Scheme VIa. The preferredα-bromoaldehyde (XIIa″) is then condensed with an appropriate thioamide,amide, or amidine derivative to form the protected thiazole, oxazole, orimidazole derivative (IXd), preferably also according to the methoddisclosed hereinabove in Scheme VIa. The protected amine derivative(IXd) so formed may then be deprotected as shown and describedhereinabove in Scheme IV.

[0270] Conventional methods and/or techniques of separation andpurification known to one of ordinary skill in the art can be used toisolate the compounds of Formula (I), as well as the variousintermediates related thereto. Such techniques will be well-known to oneof ordinary skill in the art and may include, for example, all types ofchromatography (HPLC, column chromatography using common adsorbents suchas silica gel, and thin-layer chromatography), recrystallization, anddifferential (i.e., liquid-liquid) extraction techniques.

EXPERIMENTAL

[0271] Chemical Syntheses

[0272] The embodiments of the present invention are illustrated by thefollowing Examples. It is to be understood, however, that theembodiments of the invention are not limited to the specific details ofthese Examples, as other variations thereof will be known, or apparentin light of the instant disclosure, to one of ordinary skill in the art.

Example 1

[0273] {2-[4-(4-Methyl-oxazol-2-yl)-phenoxyl-ethyl}-carbamic acid benzylester

[0274] [2-(4-Carbamoyl-phenoxy)-ethyl]-carbamic acid benzyl ester (322mg, 1.02 mmol) and 1-bromo-2,2-dimethoxypropane (3.8 g, 20.4 mmol) werecombined in a round-bottomed flask and heated to about 130° C. for aboutthirty minutes. The reaction mixture was then cooled to room temperatureand poured into water. The mixture was extracted with ethyl acetate, thecombined extracts dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude material was purified bycolumn chromatography (1:1 hexanes/ethyl acetate) to afford the desiredoxazole product (167 mg, 47% yield). LRMS ([M+H]⁺)=353.1.

Example 2

[0275]2-[4-(4-Methyl-oxazol-2-yl)-phenoxyl-ethylamine

[0276] The title compound of Example 1,{2-[4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester,(166 mg, 0.47 mmol) was dissolved in methanol (5 ml) and 10% Pd/C (50mg) and 1,4-cyclohexadiene (192 mg, 2.4 mmol) were added to theresulting solution. The mixture was allowed to stir for about sixteenhours, and then it was filtered through diatomaceous earth, and thefilter pad was washed with methanol. The filtrate was concentrated invacuo to dryness, and the resulting material (92 mg, 90% yield), whichwas determined to be pure by ¹H NMR, was used directly without furtherpurification. LRMS ([M+H]⁺)=219.2.

Example 3

[0277]4-Hydroxy-thiobenzamide

[0278] In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml)were heated with stirring to about 80° C. for about thirty minutes. Anadditional 10 ml of water was then added to the suspension, and thereaction was heated for about another one hour. The mixture was thenallowed to stir for about sixteen hours at room temperature and was thenextracted with water and 1:1 ether/ethyl acetate. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting solid was purified by column chromatography(silica gel; hexanes to ethyl acetate). The product was isolated as ayellow solid (5.54 g, 87% yield). ¹H NMR (CD₃OD): δ6.74 (d, 2H, J=9.1Hz), 7.83 (d, 2H, J=8.7 Hz).

Example 4

[0279]4-(4-Phenyl-thiazol-2-yl)-phenol

[0280] In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61mmol) and 4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved inethanol (10 ml), and the resulting solution was heated to reflux. Afterabout one hour, the reaction was cooled to about 35° C. and was allowedto stir for about an additional twelve hours. The reaction mixture wasthen concentrated in vacuo to an oil, the residue redissolved in ethylacetate and methylene chloride, and extracted with saturated aqueoussodium bicarbonate. The combined extracts were then extracted withbrine, dried over magnesium sulfate, filtered, and concentrated in vacuoto an oil. The crude product was purified by column chromatography(silica gel; methylene chloride to 2% methanol/methylene chloride). Thetitle product was isolated as a white solid (516 mg, 78% yield). LRMS([M+H]⁺)=254.1.

Example 5

[0281] Benzyl-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxyl-ethyl}-carbamate

[0282] 4-(4-Phenyl-thiazol-2-yl)-phenol (516 mg, 2.03 mmol) wasdissolved in toluene (6.8 ml), and triphenylphosphine (786 mg, 3.00mmol) and benzyl N-(2-hydroxyethyl)-carbamate (585 mg, 3.00 mmol) wereadded. The solution was cooled to about 0° C. and1,1-(azodicarbonyl)-dipiperidine (757 mg, 3.00 mmol) was added. Themixture was allowed to stir for about 10 minutes at about 0° C. and wasthen allowed to warm to room temperature. An additional 6.8 ml oftoluene and 6.8 ml of tetrahydrofuran were added to the viscoussolution. The reaction mixture was stirred for about forty-eight hours,and then the solids were filtered off and rinsed with a minimum volumeof 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuoto a semisolid which was then purified by column chromatography (silicagel; methylene chloride to 2% methanol/methylene chloride) to give 396mg of pure product (45% yield). LRMS ([M+H]⁺)=430.9.

Example 6

[0283] 2-[4-(4-Phenyl-thiazol-2-yl)-phenoxyl-ethylamine

[0284] Benzyl-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethyl}-carbamate(396 mg, 0.92 mmol) was dissolved in methylene chloride (4.6 ml) andmethanesulfonic acid (0.895 ml, 13.8 mmol) was added dropwise to give ahomogenous yellow solution. The reaction mixture was allowed to stir forabout sixteen hours, diluted with methylene chloride, and was brought tobasic pH (12-13) with 1M sodium hydroxide. The mixture was thenextracted with methylene chloride, and the combined organic extractswere dried over magnesium sulfate, filtered, and concentrated in vacuo.The resulting crude material was purified by column chromatography(silica gel; methylene chloride to 2% methanol/methylene chloride) toafford the product in 78% yield (213 mg). LRMS ([M+H]⁺)=297.2.

Example 7

[0285]Benzyl-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxyl-ethyl}-carbamate

[0286] Acetamidine hydrochloride (112 mg, 1.18 mmol),benzyl-[2-(4-bromoacetyl-phenoxy)-ethyl]-carbamate (160 mg, 0.39 mmol),and sodium ethoxide (80.3 mg, 1.18 mmol) were combined in around-bottomed flask, dissolved in ethanol, and heated to about 80° C.for about two hours. The reaction mixture was then allowed to cool toroom temperature, and the resulting heterogenous mixture was filtered.The filtrate was then concentrated in vacuo to an oil which was purifiedby column chromatography (silica gel; 5% methanol/methylene chloride to10% methanol/methylene chloride) to afford 92 mg (64% yield) of thedesired product. LRMS ([M+H]⁺)=352.2.

Example 8

[0287] 2-[4-(2-Methyl-1H-imidazol-4-yl)-phenoxyl-ethylamine

[0288] In a nitrogen-purged Parr flask,benzyl-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethyl}-carbamate (78mg, 0.22 mmol) was dissolved in methanol (15 ml), and 10% Pd/C (20 mg)was added in one portion. The material was then hydrogenated at about 45psi for about four hours. The reaction mixture was then filtered througha pad of diatomaceous earth and the filter pad was washed with methanol.The filtrate was concentrated in vacuo, and the resulting material (49mg, 100% yield) was carried on without further purification. LRMS([M+H]⁺)=218.2.

Example 9

[0289] N-[2-(4-Acetyl-phenyl)-ethyl]-acetamide

[0290] In a 500 ml flame-dried flask, N-phenethyl-acetamide (6.53 g,40.0 mmol) was dissolved in methylene chloride (65 ml), and acetylchloride (7.22 g, 92.0 mmol) was added in one portion. The resultingsolution was cooled to about 0° C., and aluminum chloride (18.1 g, 136mmol) was added in portions over about thirty minutes. The solution wasstirred for about five minutes at about 0° C., and the ice bath was thenremoved and the mixture was heated to reflux for about thirty minutes.After cooling to room temperature, the reaction mixture was poured overice water, stirred for about ten minutes, and then extracted withmethylene chloride (2×100 ml). The combined organic extracts were thenwashed sequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting white solid (7.52 g,92% yield) was ascertained to be about 90% pure by NMR, and was employeddirectly without further purification. LRMS ([M+H]⁺)=206.2.

Example 10

[0291] N-[2-(4-Bromoacetyl-phenyl)-ethyl]-acetamide

[0292] In a round-bottomed flask,N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23 g, 35.2 mmol) wasdissolved in methylene chloride (120 ml), and methanol (60 ml).Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added to thissolution in one portion, and the mixture was allowed to stir overnightat room temperature. The volatiles were then removed in vacuo to affordan oil, which was then resuspended in 100 ml of methylene chloride andextracted with 125 ml of saturated aqueous sodium bicarbonate. Theaqueous extracts were reextracted with methylene chloride (3×100 ml),and the combined organic extracts were then washed with water, driedover magnesium sulfate, filtered, and concentrated in vacuo. The crudeoil was purified by column chromatography (silica gel; methylenechloride to 7% methanol/methylene chloride), and the resulting materialwas washed with 110 ml of water to afford 8.27 g (83% yield) of pureproduct as a white solid. LRMS ([M-1 ]⁻)=283.0, 284.9.

Example 11

[0293] N-[2-[4-(2-Phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide

[0294] In a round-bottomed flask, thiobenzamide (357 mg, 2.60 mmol) andN-[2-(4-bromoacetyl-phenyl)-ethyl]-acetamide (740 mg, 2.60 mmol) werecombined in ethanol (30 ml) and heated to about 80° C. for about threehours. The reaction mixture was then concentrated in vacuo to yield anoff-white solid. The resulting material (838 mg, 100% yield) wasascertained to be pure by NMR and was carried into the next stepdirectly without further purification. LRMS ([M+H]⁺)=323.2.

Example 12

[0295] 2-[4-(2-Phenyl-thiazol-4-yl)-phenyl]-ethylamine

[0296] In a round-bottomed flask,N-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide (838 mg, 2.60mmol) was added to 5.0 ml of concentrated HCI and the resulting solutionwas heated to about 120° C. for about sixteen hours. The solution wasthen cooled to about 0° C., brought to pH 12 with 5M sodium hydroxide,and extracted with four portions of methylene chloride. The combinedorganic extracts were then washed with brine, dried over magnesiumsulfate, and concentrated in vacua. The crude material was purified bycolumn chromatography (silica gel; methylene chloride to 20%methanol/methylene chloride) to afford the product (617 mg, 85% yield).LRMS ([M+H]⁺)=281.2.

Example 13

[0297] N-(1,1-Dimethyl-2-phenyl-ethyl)-2,2,2--trifluoroacetamide

[0298] In a 500 ml flame-dried flask, phentermine hydrochloride (5.0 g,26.9 mmol) and pyridine (7.0 ml, 86.2 mmol) were dissolved in methylenechloride (100 ml). The resulting solution was cooled to about 0° C., andtrifluoroacetic anhydride (7.6 ml, 53.9 mmol) was added dropwise overabout four minutes. The solution was stirred for about five minutes atabout 0° C., and the ice bath was then removed. After stirring for aboutninety minutes at room temperature, the reaction mixture was recooled toabout 0° C. and 100 ml of saturated aqueous ammonium chloride was added.The organic and aqueous layers were then separated, and the aqueouslayer was reextracted with another 100 ml portion of methylene chloride.The combined organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingwhite solid (6.35 g, 96% yield) was used without further purification.LRMS ([M-1]⁻)=244.2.

Example 14

[0299] N-[2-(4-Acetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide

[0300] A flame-dried 250 ml flask was charged withN-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (5.93 g, 24.2mmol), acetyl chloride (4.00 g, 55.6 mmol), and methylene chloride. Theresulting solution was cooled to about 0° C., and aluminum (III)chloride (11.0 g, 82.2 mmol) was added in portions over about thirtyminutes. Over the course of the addition, the solution changed fromcolorless to greenish-brown. After the addition was complete, thesolution was heated to reflux for about thirty minutes, and was thencooled to room temperature and poured over 300 ml of ice water. Afterstirring for about ten minutes, the mixture was diluted with 125 ml ofmethylene chloride, and the layers were separated. The aqueous layer wasextracted with an additional 125 ml of methylene chloride. The combinedorganic extracts were then washed with water and brine, sequentially,and then dried over magnesium sulfate, filtered, and concentrated invacuo. The resulting oil, (6.9 g, 99% yield) which was ascertained to beabout 85% pure by NMR, was carried into the subsequent reaction withoutfurther purification. LRMS ([M+1]⁺)=288.2.

Example 15

[0301] N-[2-(Bromoacetyl-phenyl)-1,1-dimethyl-ethyll-2,2,2-trifluoroacetamide

[0302] In a round-bottomed flask,N-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (6.90 g, 21.0mmol) was dissolved in methylene chloride (66 ml) and methanol (33 ml).Tetrabutylammonium tribromide (10.6 g, 22.0 mmol) was added to thissolution in one portion, and the mixture was allowed to stir at roomtemperature overnight. The volatiles were then removed in vacuo to anoil, which was then resuspended in 100 ml of methylene chloride andextracted with 125 ml of saturated aqueous sodium bicarbonate. Theaqueous extracts were reextracted with methylene chloride (3×10 ml), andthe combined organic extracts were then washed with water and dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crude oilwas purified by column chromatography (silica gel; 60% methylenechloride/hexanes to 10% ethyl acetate/methylene chloride), and theresulting material (5.18 g) was recrystallized from hexanes to afford3.14 g (41% yield) of pure product as a fluffy white solid.

Example 16

[0303]N-{1,1-Dimethl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide

[0304] In a round-bottomed flask,N-[2-(bromoacetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide(388 mg, 1.06 mmol) and thioacetamide (80 mg, 1.06 mmol) were dissolvedin ethanol (10 ml), and the mixture was heated to about 80° C. for abouttwo and one-half hours. The reaction mixture was then concentrated invacuo to an oil which was carried into the next reaction without furtherpurification. LRMS ([M+1]⁺)=343.2.

Example 17

[0305] 1,1-Dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamine

[0306] In a round-bottomed flask,N-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide(˜362 mg, 1.06 mmol) was suspended in 7.5 ml of 2:1 (v:v)methanol/tetrahydrofuran, and 5M sodium hydroxide (3.2 ml, 15 equiv.)was added dropwise. The solution turned from colorless to golden brown,and was then allowed to stir at room temperature overnight. The reactionmixture was then concentrated in vacuo to remove volatiles, and theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The aqeuous layer was removed and was washed twicemore with ethyl acetate. The combined organic extracts were then washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo to afford the product (242 mg, 93% yield for both steps), whichwas used directly without further purification. LRMS ([M+1]⁺)=247.3.

Example 18

[0307]tert-Butyl-{2-[4-(5-methyl-4H-[1,2,4]-triazol-3-ylmethyl)-phenoxyl-ethyl}-carbamate

[0308] tert-Butyl-[2-(4-carbamoylmethyl-phenoxy)-ethyl]-carbamate (605mg, 2.05 mmol) and N,N-dimethylacetamide dimethylacetal (5 ml) werecombined and heated to about 120° C. for about ninety minutes. Theorange solution was then allowed to cool to room temperature and wasconcentrated in vacuo. The resulting oil was then dissolved in aceticacid (6 ml), and hydrazine hydrate (0.20 ml, 4.10 mmol) was added to thesolution. The mixture was heated to about 90° C. for about ninetyminutes and was then poured into water and brought to pH 7 by adding 5Msodium hydroxide. The material was then partitioned between ethylacetate and saturated aqueous sodium bicarbonate, and extracted withethyl acetate. The combined organic extracts were washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (silica gel;chloroform to 4% methanol/chloroform) to afford 403 mg (59% yield) ofthe desired product. LRMS ([M+H]⁺)=333.2.

Example 19

[0309] 2-[4-(5-Methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamine

[0310] To a solution oftert-butyl-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethyl}-carbamate(380 mg, 1.14 mmol) in methylene chloride (10 ml) was addedtrifluoroacetic acid (1.7 ml). The resulting mixture was stirred forabout thirty minutes and was then concentrated in vacuo. The resultingcrude oil was then dissolved in ethyl acetate and brought to pH 10 withaqueous sodium hydroxide. The aqueous layer was extracted with ethylacetate, and the combined organic extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo to afford120 mg (45% yield) of the amine product. LRMS ([M+H]⁺)=233.1.

Example 20

[0311] Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate

[0312] In around-bottomed flask equipped with a mechanical stirrer,4-hydroxyacetophenone (5.00 g, 36.7 mmol) was dissolved in toluene (122ml), and triphenylphosphine (14.4 g, 55.1 mmol), and benzylN-(2-hydroxyethyl)carbamate (10.8 g, 55.1 mmol) were added. The reactionmixture was cooled to about 0° C., and 1,1′-(azodicarbonyl)dipiperidine(13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed towarm to room temperature, and after stirring for about ten minutes, anadditional 122 ml of toluene and 122 ml of tetrahydrofuran were added tothe thick orange solution. The mixture was stirred for an additionaltwenty-four hours, and the solids were filtered off. The filtrate wasconcentrated in vacuo and the resulting solid was purified by columnchromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) toafford 9.68 g (84% yield) of the desired product as a white solid. LRMS([M-1]⁻)=312.2.

Example 21

[0313] Benzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate

[0314] Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate (10.2 g, 32.5 mmol)was dissolved in methylene chloride (100 ml) and methanol (50 ml), andtetrabutylamonium tribromide (15.7 g, 32.5 mmol) was added in oneportion. The reaction mixture was stirred for about sixteen hours, andthen quenched with water. The aqueous phase was extracted with ethylacetate and then washed with saturated aqeous sodium bicarbonate, andsaturated Na₂S₂O₃. The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo, and theresulting crude material was purified by column chromatography (silicagel; hexanes to 2:1 hexanes/ethyl acetate) to afford a colorless oilwhich solidified upon standing. (11.5 g, 90% yield).

Example 22

[0315] Benzyl-[2-[4-(2-methyl-oxazol-4-yl)-phenoxyl-ethyl]-carbamate

[0316] Acetamide (2.95 g, 50.0 mmol) andbenzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate (1.20 g, 3.06 mmol)were combined in a round-bottomed flask and heated to about 130° C. forabout ninety minutes. The reaction mixture was then allowed to cool toroom temperature, and the resulting orange solid was partitioned betweenethyl acetate and water and extracted three times with ethyl acetate.The combined organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingcrude solid was purified by column chromatography (silica gel; methylenechloride to 10% ethyl acetate/methylene chloride) to afford 621 mg (58%yield) of the product as a white solid. LRMS ([M+H]⁺)=353.3.

Example 23

[0317] 2-[4-(2-Methyl-oxazol-4-yl)-phenoxyl-ethylamine

[0318] A round-bottomed flask containingbenzyl-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethyl}-carbamate (788 mg,2.07 mmol) was purged with nitrogen, and 10% Pd/C (200 mg, 20 wt %),ethyl acetate (15 ml), and methanol (5 ml) were added.1,4-cyclohexadiene (0.90 ml, 9.60 mmol) was then added to the mixture,and the solution was allowed to stir at room temperature for about onehour. The reaction mixture was then filtered through a pad ofdiatomaceous earth and the filter cake was washed with methanol. Thefiltrate was concentrated in vacuo and the residue purified by columnchromatography (silica gel; methylene chloride to 20% methanol/methylenechloride) to afford 456 mg (89% yield) of the desired product. LRMS([M+H]⁺)=247.2.

Example 24

[0319] Imidodicarbonic acid,[2-[4-[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-oxoethyl]phenoxy]ethyl]-,bis(1,1-dimethylethyl)ester

[0320] In a round-bottomed flask,2-[4-(2-amino-ethoxy)-phenyl]-N-methyl-acetamide (7.78 g, 37.3 mmol) wasdissolved in dimethylsulfoxide (30 ml), and di-tert-butyl dicarbonate(12.2 g, 55.9 mmol) was added in one portion at room temperature. Afterthe reaction was stirred for about ninety minutes, dimethylaminopyridine(4.56 g, 37.3 mmol) and an additional 8.14 g (37.3 mmol) ofdi-tert-butyl dicarbonate were added. After a total of about four hours,an additional portion of dimethylaminopyridine (12.2 g, 55.9 mmol) wasadded, and the reaction was allowed to stir overnight. The mixture wasthen diluted with ether (150 ml) and poured into water (150 ml). Theaqueous phase was extracted twice with ether, and the combined organicextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo. The resulting crude material was thenpurified by column chromatography (silica gel; 5% ethyl acetate/hexanesto 35% ethyl acetate/hexanes) to afford the desired material (11.5 g,22.6 mmol).

Example 25

[0321] Benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-,hydrazide

[0322] To a round-bottomed flask containing imidodicarbonic acid,[2-[4-[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-oxoethyl]phenoxy]ethyl]-,bis(1,1-dimethylethyl)ester (3.10 g, 6.09 mmol) in methanol (30 ml) wasadded hydrazine monohydrate (1.03 ml, 21.3 mmol) dropwise. The resultingsolution was allowed to stir at room temperature overnight, and was thenconcentrated in vacuo to an oil. The residue was partitioned betweenmethylene chloride and saturated aqueous sodium bicarbonate, andextracted with methylene chloride. The crude material was purified bycolumn chromatography (silica gel; methylene chloride to 5%methanol/methylene chloride) to afford 1.63 g (65% yield) of the desiredproduct as an oil which crystallized upon standing.

Example 26

[0323] Benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-,2-benzoylhydrazide

[0324] To a solution of benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-, hydrazide (760mg, 1.86 mmol) in dichloromethane (20 ml) was added benzoyl chloride(0.258 ml, 2.22 mmol) and triethylamine (0.310 ml, 2.22 mmol). Theresulting solution was stirred for about twenty-four hours, quenchedwith saturated aqueous sodium bicarbonate, and extracted with methylenechloride. The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford a crude solid.This material was purified by column chromatography (silica gel; hexanesto 50% ethyl acetate/hexanes) to afford 451 mg (47% yield) of theproduct as a white solid. LRMS ([M-H]⁻)=512.1.

Example 27

[0325] 2-[4-(5-Phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine

[0326] To a solution of benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-,2-benzoylhydrazide (435 mg, 0.847 mmol) in methylene chloride (12 ml)was added pyridine (0.150 ml, 1.86 mmol). The mixture was cooled toabout −10° C., and triflic anhydride (0.299 ml, 1.78 mmol) was addeddropwise. After the addition was complete, the cold bath was removed andthe reaction mixture was stirred for about an additional one hour. Thereaction was then quenched with saturated aqueous sodium bicarbonate andextracted three times with methylene chloride. The combined extractswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (silica gel; methylene chloride to 20% methanol/methylenechloride) to afford 60 mg (25% yield) of the product amine. LRMS([M+H]⁺)=296.1.

Example 28

[0327] 6-(4-Fluoro-phenyl)-4,5-dihydro-2H-pyridazin-3-one

[0328] In a round-bottomed flask, 4-(4-fluoro-phenyl)-4-oxo-butyric acid(4.90 g, 25.0 mmol) and hydrazine hydrate (1.70 ml, 35.0 mmol) weredissolved in ethanol (50 ml), and the reaction mixture was heated toabout 80° C. for about ninety minutes. The mixture was allowed to coolto room temperature and then concentrated in vacuo. The resulting solidswere suspended and stirred in ethanol (10 ml) for ten minutes and themixture was then filtered to give pure product (4.14 g, 21.5 mmol, 86%yield). LRMS ([M+H]⁺)=193.2; m.p. 191-193° C.

Example 29

[0329] 6-[4(2-Amino-ethoxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one

[0330] In a flame-dried, round-bottomed flask, ethanolamine (1.7 ml,28.1 mmol) was dissolved in dimethylsulfoxide (9.5 ml), and potassiumtert-butoxide (95%, 3.3 g, 28.1 mmol) was added to the solution. Thismixture was stirred at about 65° C. for about ten minutes, and then6-(4-fluorophenyl)-4,5-dihydro-2H-pyridazine-3-one (3.6 g, 18.7 mmol)was added. This dark-colored solution was heated to about 80° C. forabout twelve hours, and was then cooled to room temperature. Water wasadded, and the resulting tan solid was removed by filtration. This crudesolid was then purified by column chromatography (silica gel; 5%methanol/dichloromethane to 15% methanol/dichloromethane) to afford theproduct as a white solid (1.5 g, 34% yield). LRMS ([M+H]⁺)=234.2.

Example 30

[0331] 1-(4-Methoxy-phenyl)-1H-pyrazole

[0332] Copper (II) acetate (960 mg, 5.28 mmol) was added to aflame-dried flask charged with pyrazole (240 mg, 3.52 mmol),4-methoxyphenylboronic acid (1.07 g, 7.04 mmol), 4 A molecular sieves(1.35 activated powder), and pyridine (570 μl, 7.04 mmol) in methylenechloride. The reaction was stirred for approximately two days at roomtemperature and then filtered through diatomaceous earth. The filtratewas concentrated in vacuo and purified by column chromatography (silicagel; isocratic 8% ethyl acetate/hexanes) to yield 381 mg (2.18 mmol, 62%yield) of the title compound. LRMS ([M+H]⁺)=175.2.

Example 31

[0333] 4 Pyrazole-1-yl-phenol

[0334] The title compound of Example 30,1-(4-Methoxy-phenyl)-1H-pyrazole (400 mg, 2.30 mmol), was dissolved inmethylene chloride (8 ml) and the solution was cooled to −78° C. Borontribromide (1.0 M in methylene chloride, 5.05 ml) was added dropwise tothe solution over about five minutes to afford a brown-colored solution.The reaction mixture was allowed to stir for about thirty minutes, thecooling bath was removed, and the mixture was allowed to stir at roomtemperature for about an additional three hours. The mixture was pouredinto water, and the resulting mixture was adjusted to about pH 8. Themixture was extracted with methylene chloride (3×25 ml), and thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo. The resulting crude material was purified bycolumn chromatography (25% ethyl acetate/hexanes) to afford 183 mg (50%yield) of the desired product as an oil. LRMS ([M+H]⁺)=161.1.

Example 32

[0335] 2-(4-Pyrazole-1-yl-phenoxy)-ethylamine

[0336] A round-bottomed flask was charged with 4-pyrazole-1-yl-phenol(175 mg, 1.09 mmol), and 3.6 ml of toluene, triphenylphosphine (430 mg,1.64 mmol), and benzyl N-(2-hydroxyethyl)carbamate (320 mg, 1.64 mmol)were then added. The solution was cooled to 0° C. and1,1′-(azodicarbonyl)-dipiperidine (414 mg, 1.64 mmol) was added. Themixture was allowed to stir for about ten minutes at about 0° C. and wasthen allowed to warm to room temperature. An additional 3.6 ml oftoluene and 3.6 ml of tetrahydrofuran were added to the viscoussolution. The reaction mixture was stirred for about forty-eight hours,and the precipitated solids were filtered off and washed with a minimumvolume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated invacuo to afford the intermediate[2-(4-pyrazole-1-yl-phenoxy)-ethyl]-carbamic acid benzyl ester as an oilwhich was used directly in the next step.

[0337] The crude benzyl ester above (1.23 g) was dissolved in methanol(5 ml), and 10% Pd/C (350 mg) and ammonium formate (315 mg, 5.0 mmol)were added to the resulting mixture. The mixture was allowed to stir forabout sixteen hours, and was then filtered through diatomaceous earth.The filtrate was concentrated to dryness in vacuo, and the residue wasthen suspended in water and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting crude material was purified by columnchromatography (15% methanol/methylene chloride) to afford 130 mg (57%yield for both steps) of desired product.

Example 33

[0338] 2-[4-(5-Trifluoromethyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine

[0339] In a flame-dried, round-bottomed flask, ethanolamine (836 mg,13.7 mmol) was dissolved in dimethylsulfoxide (2.7 ml), and potassiumtert-butoxide (95%, 1.54 g, 13.7 mmol) was added to the solution. Thismixture was stirred at about 65° C. for about ten minutes, and then5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole (630 mg, 2.74 mmol)was added. The dark-colored solution was heated to about 85° C. forabout eighteen hours, and was then allowed to cool to room temperature.Water was added, and the resulting tan-colored solid was collected byfiltration. This crude product was purified by column chromatography (5%methanol/dichloromethane to 20% methanol/dichloromethane) to afford theproduct as a white solid (255 mg, 25% yield). LRMS ([M+H]⁺)=272.2.

Example 34

[0340] 4-[1,2,3]Thiadiazol-4-yl-phenol

[0341] 4-(4-methoxy-phenyl)-[1,2,3]thiadiazole (1.06 g, 5.50 mmol) wasdissolved in methylene chloride (20 ml) and the solution was cooled toabout −78° C. Boron tribromide (1.0 M in methylene chloride, 12.1 ml)was added dropwise to the solution to afford a brown-colored solution.The reaction mixture was allowed to stir for about fifteen minutes, thecooling bath was removed, and the mixture was allowed to stir at roomtemperature for about an additional twelve hours. The mixture was pouredinto water, and the resulting mixture was adjusted to about pH 6. Themixture was extracted with methylene chloride (3×100 ml), and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 924 mg (94% yield) of the desired titlecompound as a tan solid. LRMS ([M+H]⁺)=179.1.

Example 35

[0342] 2-(4-[1,2,3]Thiadiazol-4-yl-phenoxy)-ethylamine

[0343] A round-bottomed flask was charged with4-[1,2,3]thiadiazol-4-yl-phenol (875 mg, 4.90 mmol), and 16 ml oftoluene, triphenylphosphine (1.93 g, 7.36 mmol), and benzylN-(2-hydroxyethyl) carbamate (1.44 g, 7.36 mmol) were added. Thesolution was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (1.86g, 7.36 mmol) was added. The mixture was allowed to stir for about tenminutes at about 0° C. and was then allowed to warm to room temperature.An additional 16 ml of toluene and 16 ml of tetrahydrofuran were addedto the viscous solution. The reaction mixture was stirred for aboutforty-eight hours, and the precipitated solids were filtered off andwashed with a minimum volume of 1:1 toluene/tetrahydrofuran. Thefiltrate was concentrated in vacuo to afford crude product which waspurified by column chromatography (50% hexanes/ethyl acetate) to provide[2-(4-[1,2,3]thiadiazol-4-phenoxy)-ethyl]-carbamic acid benzyl ester(3.0 g, 57% yield).

[0344] The purified benzyl ester above was dissolved in methylenechloride (7 ml), and methanesulfonic acid (1.35 ml, 20.9 mmol) was addedto the solution. The resulting solution was heated to about 35° C. forabout two hours, and was then diluted with methylene chloride and water.The pH was adjusted to about 12 with 5N sodium hydroxide, and themixture was extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting crude material was purified by columnchromatography (20% methanol/methylene chloride) to afford 168 mg (59%yield) of desired amine product. LRMS ([M+H]⁺)=222.2.

Example 36

[0345] 4-(4-Methoxy-phenyl)-isoxazole

[0346] A round-bottomed flask was charged with potassium carbonate (1.45g, 10.5 mmol) and ethanol (14 ml). To this mixture was addedhydroxylamine hydrochloride (730 mg, 10.5 mmol), and2-(4-methoxyphenyl)-malondialdehyde (1.25 g, 7.00 mmol). The reactionmixture was heated at about 80° C. for about three hours. The reactionmixture was then concentrated in vacuo to approximately one-quartervolume and partitioned between water and ethyl acetate. The mixture wasextracted with ethyl acetate and the combined organic extracts weredried over magnesium sulfate, filtered, and concentrated in vacuo to adark oil. This crude material was purified by column chromatography (10%ethyl acetate/hexanes) to afford 1.06 g (86% yield) of the desiredproduct. LRMS ([M-H]⁻)=174.1.

Example 37

[0347] 4-Isoxazol-4-yl-phenol

[0348] To a round-bottomed flask was added D,L-methionine (1.30 g, 8.73mmol), 4-(4-methoxy-phenyl)-isoxazole (1.02 g, 5.82 mmol), andmethanesulfonic acid (24 ml). The resulting solution was heated to about70° C. for about eighteen hours, and was then allowed to cool to roomtemperature and poured onto ice water. The mixture was adjusted to aboutpH 4, and the heterogenous mixture was filtered. The solid was washedwith water and then dried to yield the title compound as an off-whitesolid (640 mg, 68% yield). LRMS ([M-H]⁻)=160.0.

Example 38

[0349] [2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester

[0350] A round-bottomed flask was charged with 4-isoxazole-4-yl-phenol(570 mg, 3.54 mmol), and 12 ml of toluene, triphenylphosphine (1.39 g,5.30 mmol), and benzyl N-(2-hydroxyethyl) carbamate (1.04 g, 5.30 mmol)were added. The solution was cooled to about 0° C. and1,1′-(azodicarbonyl)-dipiperidine (1.34 g, 5.30 mmol) was added. Themixture was allowed to stir for about ten minutes at about 0° C., andthe solution was then allowed to warm to room temperature. An additional12 ml of toluene and 12 ml of tetrahydrofuran were added to the viscoussolution. The reaction mixture was stirred for about twenty-four hours,and then the precipitated solids were filtered off and washed with aminimum volume of 1:1 toluene/tetrahydrofuran. The filtrate wasconcentrated to afford the crude product which was purified by columnchromatography (30% ethyl acetate/hexanes) to afford the desired productas a white solid (1.06 g, 88% yield).

Example 39

[0351] 2(4-Isoxazol-4-yl-phenoxy)-ethylamine

[0352] [2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester(1.00 g, 2.81 mmol) was dissolved in methylene chloride (14 ml) andmethanesulfonic acid (2.73 ml, 42.2 mmol) was added. The resultingmixture was heated to about 35° C. for about two hours, and was thendiluted with methylene chloride and water. The pH of the mixture wasadjusted to about 12 with 5N sodium hydroxide, and the mixture wasextracted with methylene chloride. The combined extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingcrude product was purified by column chromatography (20%methanol/methylene chloride) to afford 202 mg (53% yield) of the desiredamine. LRMS ([M+H]⁺)=205.3.

[0353] The compounds of Formula (I) may be prepared according to thethree general preparative methods outlined hereinabove in Schemes I, IIand III, denoted hereinbelow as Method A, Method B, and Method C,respectively, using appropriate synthetic precursors, including thoseprecursors disclosed hereinabove in Examples 1 through 38, or thoseanalogous thereto.

[0354] Method A (Scheme I)

[0355](R)-1-(6-Chloro-pyridin-3-yl)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol

[0356] In a round-bottomed flask, (R)-2-chloro-5-oxiranyl-pyridine (U.S.Pat. No. 5,541,197) (73.0 mg, 0.477 mmol) and the title compound ofExample 4 (2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine) (212 mg,0.716 mmol) were dissolved in 5 ml of ethanol, and the mixture washeated to about 80° C. for about sixteen hours. The solution was thenconcentrated in vacuo to an oil, and the crude material was purified bycolumn chromatography (methylene chloride to 2% methylenechloride/methanol) to afford 107 mg (0.236 mmol, 50%) of the titlecompound as a white solid. LRMS ([M+H]⁺)=452.2.

[0357] Utilizing appropriate starting materials, the following compoundswere prepared in a manner analogous to that employed for the preparationof the title compound of Method A:

[0358](R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

[0359](R)-2-{2-[4-(4-biphenyl-4-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

[0360](R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

[0361](R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

[0362](R)-N-[2-chloro-5-(2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0363](R)-N-[2-chloro-5-(2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0364](R)-N-(2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0365](R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0366](R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0367](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0368](R)-N-(2-chloro-5-{1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0369](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0370](R)-N-(2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0371](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0372](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

[0373](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0374](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0375](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

[0376](R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

[0377](R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino3-ethyl)-phenyl]-methanesulfonamide;

[0378](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-cyclopentyl-thiazol-4-y)-phenoxy]-ethylamino}-ethanol;

[0379](R)-1-(6-chloro-pyridin-3-yl)-2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0380](R)-1-(6-chloro-pyridin-3-yl)-2-[1,1-dimethyl-2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethanol;

[0381](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0382](R)-1-(6-chloro-pyridin-3-yl)-2-[1,1-dimethyl-2-(4-oxazol-5-yl-phenoxy)-ethylaminol-ethanol;

[0383](R)-1-(6-chloro-pyridin-3-yl)-2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0384](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0385](R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0386](R)-1-(6-chloro-pyridin-3-yl)-2-2-[3-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0387](R)-1-(6-chloro-pyridin-3-yl)-1-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

[0388](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0389](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0390](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-ethanol;

[0391](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0392](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0393](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0394](R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl-phenoxy}-ethylamino)-ethanol;

[0395](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-ethanol;

[0396](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0397](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-]-ethylamino}-ethanol;

[0398](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0399](R)-1-(6-chloro-pyridin-³-yl)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0400](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy-ethylamino}-ethanol;

[0401](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-methyl-thiazol-4-y)-phenoxy]-ethylamino}-ethanol;

[0402](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0403](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0404](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamino}-ethanol;

[0405](R)-1-(6-chloro-pyidin-3-yl)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylaminol-ethanol;

[0406](R)-1-(6-chloro-pyridin-3-yl)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-ethanol;

[0407](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0408](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0409](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamino}-ethanol;

[0410](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

[0411](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0412](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0413](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0414](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0415](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-ethanol;

[0416](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0417](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0418](R)-1-(6-chloro-pyridin-3-y)-2-{2-[3-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0419](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0420](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0421](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy-ethylamino}-ethanol;

[0422](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0423](R)-1-(6-chloro-pyridin-3-y)-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

[0424](R)-1-(6-chloro-pyridin-3-yl)-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

[0425](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0426](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0427](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0428](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

[0429](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0430](R)-1-(6-chloro-pyridin-3-yl)-2-(2-{3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0431](R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0432](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0433](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;and

[0434](R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol.

[0435] Method B (Scheme II)

[0436](R)-N-[5-(1-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide

[0437] In a round-bottomed flask,2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine (175 mg, 0.747 mmol)and toluene-4-sulfonic acid2-(6-acetylamino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethylester (231 mg, 0.498 mmol) were dissolved in dimethylsulfoxide (0.50mL), and diisopropyl ethyl amine (0.105 mL, 0.600 mmol) was added in oneportion. The resulting mixture was heated to about 80° C. for aboutsixteen hours, and was then partitioned between diethyl ether and water.The aqueous phase was extracted with diethyl ether four times, and thecombined organic extracts were then washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingwhite solid was purified by column chromatography (methylene chloride to10% methanol/methylene chloride) to afford 117 mg (45%) of the desiredproduct. LRMS ([M+1]⁺): 527.1.

[0438](R)-N-[5-(1-Hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide

[0439] To a solution of(R)-N-[5-(1-(tert-butyl-dimethyl-silanyloxy)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide(115 mg, 0.218 mmol) in tetrahydrofuran (1.5 mL) was addedtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.65 mL, 0.65mmol) at room temperature. The resulting solution was allowed to stirfor about two and one-half hours, and the reaction mixture was thenpartitioned between ethyl acetate and water. The pH of the mixture wasadjusted to about 10-11, and the aqueous phase was then extracted withethyl acetate. The combined organic extracts were washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting crude material was purified by column chromatography(methylene chloride to 20% methanol/methylene chloride) to afford 75 mg(83%) of the desired product. LRMS ([M+1]⁺): 413.2.

[0440](R)-1-(6-Amino-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol

[0441] In a round-bottomed flask,(R)-N-[5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide(74 mg, 0.18 mmol) was dissolved in 1.0 mL of ethanol, and 1.0 mL of 2 Msodium hydroxide was added to the solution. The reaction mixture wasthen heated to about 80° C. for about twenty minutes, and was thendiluted with water and adjusted to about pH 11. The aqueous phase wasextracted with four portions of methylene chloride, and the combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude material was purified bycolumn chromatography (methylene chloride to 20% methanol/methylenechloride) to afford 49 mg (74%) of the desired product. LRMS ([M+1]⁺):371.2.

[0442] Method C (Scheme III)

[0443]2-{2-[4-(4-Phenyl-thiazol-2-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol

[0444] In a nitrogen-purged round-bottomed flask,1-(6-chloro-pyridin-3-yl)-2-{2-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol(107 mg, 236 mmol) was dissolved in a mixture of methanol (2.3 ml), THF(0.5 ml), and ethyl acetate (0.5 ml). Palladium on carbon (10%, 107 mg,100 wt %) and ammonium formate (149 mg, 2.36 mmol) were then addedsequentially. The reaction mixture was stirred overnight, filteredthrough diatomaceous earth, and the filter cake rinsed with ethylacetate. The filtrate was concentrated to a white solid, which waspurified by column chromatography (methylene chloride to 4%methanol/methylene chloride) to afford a pale yellow solid (44 mg, 44%).LRMS ([M+H]⁺)=418.3.

[0445] Utilizing appropriate starting materials, the following compoundswere prepared in a manner analogous to that employed for the preparationof the title compound of Method C:

[0446](R)-1-(6-amino-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0447](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0448](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0449](R)-1-pyridin-3-yl-2-{2-[3-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0450](R)-1-pyridin-3-yl-2-{2-[3-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0451](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol4-yl)-phenoxy]-ethylamino}-ethanol;

[0452](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0453](R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0454] (R)-1-pyridin-3-yl-2-[2-(4-[1,2,3]thiadiazol-5-ylphenoxy)-ethylamino]-ethanol;

[0455](R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

[0456](R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

[0457](R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0458](R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0459](R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

[0460](R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0461] (R)-1-pyridin-3-yl-2-{2-[4-(4H[1,2,4-]triazol-3-yl)-phenoxy]-ethylamino}-ethanol;

[0462](R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

[0463](R)-1-pyridin-3-yl-2-(2-{3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0464] (R)-l-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

[0465](R)-1-pyridin-3-yl-2-{2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamino}-ethanol;

[0466](R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;ethanol;

[0467](R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

[0468](R)-2-{2-[4-(2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0469](R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0470](R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0471](R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0472](R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0473](R)-2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

[0474](R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0475](R)-2-[1,1-dimethyl-2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0476](R)-2-[1,1-dimethyl-2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0477](R)-2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

[0478](R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0479](R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0480](R)-2-{2-[3-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0481](R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0482](R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0483](R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-1-pyridin-3-yl-ethanol;

[0484](R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

[0485](R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0486](R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;

[0487](R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0488](R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0489](R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0490](R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0491](R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0492](R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0493](R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0494](R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0495](R)-2-[2-(3-methyl-4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0496](R)-2-{2-[4-(2-methyl-oxazol4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0497](R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol;

[0498](R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

[0499](R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0500](R)-2-{2-[4-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0501](R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0502](R)-2-{2-[3-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0503](R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0504] (R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

[0505](R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0506](R)-2-[2-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0507](R)-2-[2-(4-oxazol-2-yl-phenoxy)-ethylamino]-1-pyridin-3-ylethanol;

[0508](R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0509](R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

[0510](R)-2-{2-[4-(2-phenethyl-thiazol-4-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol;

[0511](R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0512](R)-2-{2-[3-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0513](R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0514](R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

[0515](R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0516](R)-2-{2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0517](R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

[0518](R)-2-[2-(4-pyrazol-3-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;and

[0519](R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol.

[0520] Salt Formation

[0521] The hydrochloride salt forms of the compounds of Formula (I) maybe prepared according to the following example.

[0522] The compound(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol(40 mg, 0.095 mmol) was dissolved in about 3 ml of methylene chloride,and 1.0 M HCI in diethylether (0.28 ml, 0.28 mmol) was added to thesolution dropwise. The resulting cloudy suspension was concentrated invacuo to afford 47 mg of a white solid.

[0523] Biological Assays

[0524] The utility of the compounds of Formula (I), the stereoisomersand prodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs in the practice of the instantinvention, can be evidenced by activity in at least one of the protocolsdescribed hereinbelow.

Assay 1

[0525] β₃ Receptor Selectivity Over β₁ and β₂ Adrenergic Receptors

[0526] In vitro β₃ receptor agonist activity and selectivity over β₁ andβ₂ adrenergic receptors may be determined by measurement of cyclicadenosine monophosphate (cAMP) accumulation in Chinese hamster ovarycells.

[0527] Chinese hamster ovary cells uniquely transfected with the cDNAfor the human β₁, β₂, or β₃ adrenergic receptor are grown to confluencein Ham's F12 media (Gibco BRL, Life Technologies, Inc., Grand Island,N.Y.) containing 10% fetal bovine serum, 500 mg/ml geneticin, 100 U/mlpenicillin, 100 mg/ml streptomycin, and 250 ng/ml fungizone according tothe procedure described in American Type Culture Catalog of Cell Linesand Hybridomas, Seventh Edition, 1992, p. 36, ATCC CCL 61 CHO-K1.Compounds are prepared as 25 mM stock solutions in DMSO (0.1% DMSO finalconcentration), diluted in Ham's F12 media and added to the cells at10⁻¹⁰ to 10⁻⁵ M along with 10⁻⁵ M isobutylmethylxanthine to inhibitphosphodiesterase activity. The media and cells are then incubated forsixty minutes at 37° C. At the end of the incubation period, the mediais aspirated and the cells lysed in 0.01 N HCI. The cellular content ofcAMP is then determined by radioimmunoassay (RIA) using a kit from NewEngland Nuclear (Burlington, Mass.). There is a direct correlationbetween the cellular content of cAMP and the agonism of the β₁, β₂, orβ₃ adrenergic receptor. The non-selective, full β-adrenergic agonistisoproterenol is included as a positive control at 10⁻⁵ M.

Assay 2

[0528] Many G protein-coupled receptors (GPCRs) exhibit at least twoagonist affinity states. High affinity agonist binding to GPCRs requiresthe association or coupling of the receptor with the GDP-boundheterotrimeric G protein complex. In general, the low affinity agonistbinding site is indicative of the uncoupled receptor state. The highaffinity agonist binding site can be converted to the low affinity siteby addition of GTP or its analogs. In the absence of agonist, G proteinsdisplay high affinity for GDP. In the presence of agonist, G proteinsdisplay high affinity for GTP. Thus, when agonist and GTP are added tothe receptor/G protein complex, GTP displaces GDP and uncouples thereceptor from the G protein. Two affinity states for agonists can bedetected in radioligand comptetetion binding assays. A two-site fit isgenerally observed for agonists for many GPCRs and can be calculatedusing commercially available software. The high affinity site (K_(iH))corresponds to the G protein-coupled state and, in the case ofβ₃-adrenergic receptors correlates well with the functional ED₅₀ forstimulation of cAMP accumulation.

[0529] In order to identify compounds that attenuate the binding of[¹²⁵I]cyanopindolol (ICYP) to β₃ adrenergic receptors, the followingradioligand binding assay can be used.

[0530] Radioligand Binding Assays

[0531] ICYP β₃ Adrenergic Receptor Competition Binding Assay

[0532] The specific activity of [¹²⁵I]CYP is 2000 Ci/mmole. ICYPundergoes catastrophic decay upon radiolysis. Therefore, the specificactivity always remains at 2000 Ci/mmole, but the concentration willdecrease over time. The final concentration of ICYP is 250 pM.Therefore, a 2.5 nM (10 x) stock needs to be made. [¹²⁵I]CYP can beobtained from New England Nuclear, Boston, Mass.

[0533] Competitors

[0534] Up to four compounds can be tested in thirteen competition curvesin a 96 well format. An example for a single compound is outlined below.

[0535] [Comp 1]

[0536] A 1,2 −10

[0537] B 1,2 −9.3

[0538] C 1,2 −9

[0539] D 1,2 −8.3

[0540] E 1,2 −8

[0541] F 1,2 −7.3

[0542] G 1,2 −7

[0543] H 1,2 −6.3

[0544] A 3,4 −6

[0545] B 3,4 −5

[0546] C 3,4 −4

[0547] D 1,3 pindolol

[0548] E 3,4 TOTAL

[0549] The next compound would begin in F 3,4. Two pairs of totals andnon-specific binding are added to the plates.

[0550] Wells E 3,4 and G 7,8 are for total cpm bound.

[0551] Wells D 3,4 and H 7,8 are for 100 μM pindolol to determinenon-specific binding.

[0552] To each well in order add:

[0553] 20 μl buffer to “total” wells

[0554] 20 μl 1 mM pindolol to pindolol wells

[0555] 20 μl of each concentration of compound to the appropriate wells

[0556] 20 μl of 2.5 nM ICYP to all wells

[0557] 160 μl membranes diluted to 15 μg/160 μl

[0558] Procedure

[0559] 1. Set up assay for Packard 96 well Unifilter with GF/C filters(Packard; Meriden, Conn.) using a 96 well microtiter plate.

[0560] 2. Incubate 90-120 minutes with shaking at room temperature

[0561] 3. Using Packard cell harvester (Packard; Meriden, Conn.),aspirate samples into processing head. Use a pre-soaked (0.3% PEI)filter.

[0562] 4. Wash four times with cold wash buffer.

[0563] 5. Dry plate, and add 25 μl Microscint (ICN Manufacturers; CostaMesa, Calif.) to each well.

[0564] 6. Count samples in Wallac beta plate reader (Wallac; Turku,Finland).

[0565] Binding Buffer

[0566] 50 mM Hepes/10 mM MgCl₂, pH 7.4 (prepared from 10 x stocksolution) 0.2 % BSA (fraction V)

[0567] Protease inhibitors (prepared as 100 x stock solution)

[0568] 100 μg/ml bacitracin

[0569] 100 μg/ml benzamidine

[0570] 5 μg/ml aprotin

[0571] 5 μg/ml leupeptin

[0572] Wash Buffer

[0573] 50 nM Hepes/10 mM MgCl₂, pH 7.4, ice cold (prepared from 10 xstock solution)

Assay 3

[0574] Oxygen Consumption

[0575] As will be well known to one of ordinary skill in the art, duringincreased energy expenditure, animals generally consume increasedamounts of oxygen. In addition, metabolic fuels such as, for example,glucose and fatty acids, are oxidized to CO₂ and H₂O with theconcomitant evolution of heat, an effect commonly referred to in the artas thermogenesis. Accordingly, the measurement of oxygen consumption inanimals, including humans and companion animals, is an indirect measureof thermogenesis, and indirect calorimetry may be commonly used inanimals, e.g., humans, by one of ordinary skill in the art, to measuresuch energy expenditures.

[0576] The ability of the compounds of Formula (I), the stereoisomersand prodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs, to generate a thermogenicresponse may be demonstrated according to the following protocol usingmale Sprague-Dawley rats (Charles River, Wilmington, Mass.).

[0577] Whole animal oxygen consumption may be measured using an opencircuit, indirect calorimeter (Oxymax™, Columbus Instruments, Columbus,Ohio). The gas sensors are calibrated with nitrogen gas and gas mixture(0.5% carbon dioxide, 20.5% oxygen, 79% nitrogen; Abco IndustrialSupplies, Waterford, Conn.) before each experiment. Male Sprague-Dawleyrats (300-380 g body weight) are placed in sealed chambers (43×43×10 cm)of the calorimeter and the chambers placed in activity monitors. Airflow rate through the chambers is set at 1.6-1.7 I/min. The calorimetersoftware calculates the oxygen consumption (ml/kg/hour) based on theflow rate of air through the chambers and the difference in oxygencontent at inlet and outlet ports. The activity monitors have fifteeninfrared light beams spaced one inch apart on each axis; ambulatoryactivity is recorded when two consecutive beams are broken (repeatedinterruptions of the same beam are not registered) and the results arerecorded as counts. Basal oxygen consumption and ambulatory activity aremeasured every ten minutes for two and one-half to three hours. At theend of the basal period, the chambers are opened and the test compound(0.01-20 mg/kg, prepared in water, 0.5% methyl cellulose, or othersuitable vehicle) or an equivalent amount of vehicle is administered byoral gavage. Oxygen consumption and amulatory activity are measuredevery ten minutes for an additional two to six hours post-dosing.Percent change in oxygen consumption is calculated by averaging thepost-dosing values and dividing by basal oxygen consumption (average ofthe pre-dosing values except the first hour). Oxygen consumption valuesobtained during time periods where ambulatory activity exceeds 100counts are excluded from the calculation. Thus, the values represent %change in resting oxygen consumption.

Assay 4

[0578] Hypoglycemic Activity

[0579] The compounds of Formula (I) may be tested for hypoglycemicactivity accoprding to the following procedure, and as an aid indetermining dosages when compared to other test compounds and standards.

[0580] Five to eight-week old C57 BL/6J-ob/ob mice (Jackson Laboratory,Bar Harbor, Me.) are housed five animals per cage at an ambienttemperature of 66° C. under standard animal care practices. After a oneweek acclimation period, the animals are weighed and 25 microliters ofblood is collected via an occular bleed prior to any treatment. Theblood sample is immediately diluted 1:5 with saline containing 2% sodiumheparin, in tubes held on ice. Blood samples are centrifuged for twominutes to remove red blood cells and the supernatant is analyzed forglucose concentration using a clinical autoanalyzer (Abbott Spectrum®CCx; Abbott Laboratories, Abbott Park, Ill.). Animals are thenregrouped, in groups of five animals per cage, such that the meanglucose values of the groups are similar. The mice are then dosed onceor twice daily for five days with test compound (0.01-20 mg/kg), with apositive control such as englitazone or ciglitazone (50 mg/kg p.o.)(U.S. Pat. No. 4,467,902; Sohda et al., Chem. Pharm. Bull., 32,4460-4465, (1984)), or with vehicle. All compounds are administered byoral gavage in a vehicle consisting of 0.5% w/v methyl cellulose, orwith other suitable vehicle. On Day 5, the animals are weighed again andbled (via the occular route) for blood glucose levels as describedhereinabove. Plasma glucose is then calculated by the equation:

Plasma Glucose (mg/dl)=Sample Value×5×1.67=8.35×Sample Value where 5 isthe dilution factor and 1.67 is the plasma hematocrit adjustment(assuming the hematocrit is 40%).

[0581] The animals dosed with vehicle maintain substantially unchangedhyperglycemic glucose levels (e.g. 300 mg/dl), while positive controlanimals have depressed glucose levels (e.g. 130 mg/dl). The glucoselowering activity of test compounds is expressed in terms of % glucosenormalization. For example, a glucose level which is the same as thepositive control is expressed as 100%.

Assay 5

[0582] β₁ and β₂ Receptor Selectivity

[0583] In vivo selectivity for β₁ and β₂ receptors may be determined bymeasurements of heart rate, blood pressure, and plasma potassiumconcentration gathered on conscious catheterized rats (male,Sprague-Dawley, 300-400 g body weight). To implant catheters, rats areanesthetized with pentobarbital (50-60 mg/kg i.p.) and the left carotidartery is cannulated with PE50 tubing. The catheter is tunneledsubcutaneously, exteriorized at the back of the neck, filled with asolution of polyvinylpyrrolidone in heparinzied saline, flame sealed,and taped. Experiments are performed seven days after surgery. On theday of the experiment, the catheters are untaped and flushed withsaline. After at least thirty minutes, basal values for heart rate andblood pressure are measured by attaching the catheter to a pressuretransducer, the results recorded on a Grass Model 7 polygraph (GrassMedical Instruments, Quincy, Mass.), and a basal blood sample (0.5 ml)is obtained from the arterial catheter. After obtaining basal values,the test compound or vehicle is administered by oral gavage and bloodpressure (measure of β₂ activity) and heart rate (measure of β₁activity) measurements are taken at 15, 30, 45, and 60 minutes, andblood samples for potassium determination (β₂) are obtained at 30 and 60minutes. Isoproterenol, a non-selective β-agonist, can be tested as apositive control at doses ranging from 0.001 to 1 mg/kg (injected s.c.in saline vehicle). Plasma potassium is determined by flamespectrophotometry. To determine changes, basal values are subtractedfrom the average of the post-dosing values.

Assay 6

[0584] Reducing Intestinal Motility

[0585] The compounds of Formula (I) have the effect of reducingintestinal motility and thus have utility in aiding in the treatment ofvarious gastrointestinal disorders such as irritable bowel syndrome,peptic ulceration, esophagitis, gastritis, duodenitis (including thatinduced by Helicobacter pylori), intestinal ulcerations (includinginflammatory bowel disease, ulcerative colitis, Crohn's Disease andproctitis), and gastrointestinal ulcerations. It has been proposed thatthe motility of non-sphincteric smooth muscle contraction is mediated byactivity at β₃ adrenergic receptors. The availability of a β₃ specificagonist, with little activity at β₁ and β₂ receptors, will assist in thepharmacologic control of intestinal motility without concurrentcardiovascular effects.

[0586] In vivo activity of the compounds of Formula (I) for thetreatment or prevention of intestinal motility disorders can bedetermined according to the following procedures. Eighteen-hour fastedmale Sprague-Dawley derived (CD) rats (175-225 g) are dosed with 0.01-20mg/kg p.o. of test compound or vehicle (distilled water). Thirty minutesafter administration of test compound, the rats are orally dosed with0.25 ml of a solution of sodium chromate in 0.9% saline containing about20,000 cpm of ⁵¹Cr (specific activity 350 mCi/mg Cr). Twenty minuteslater, the rats are sacrificed, the gastroesophageal, pyloric, andileocecal junctions are then ligated, and the stomachs and smallintestines are removed. The small intestines are then divided into tenequal lengths, and the stomach and each length of intestine assayed forradioactivity with a gamma counter. Gastric emptying rate may then bedetermined for each rat by comparing the amount of radioactivity in theintestine relative to the total in the intestine plus stomach. Inaddition, the geometric center of the distribution of the radioactivemarker is then used as a measure of the overall transit rate through thestomach and intestine. The geometric center is calculated by summing theproducts of the fractions of ⁵¹Cr in each segment times the segmentsnumber: geometric center=S ((fraction of ⁵¹Cr per segment)×(segmentnumber)). For these calculations, the stomach is considered segmentnumber 0, and and the ten intestinal segments as numbers 1 to 10. Thus,a geometric center of 0.0 indicates that the entire load of ⁵¹Cr remainsin the stomach. Data from the two experiments are pooled, andstatistical evaluations are made using Dunnett's multiple comparisontest.

[0587] Alternatively, in groups of eight, overnight-fasted maleSprague-Dawley (CD) rats (175-225 g) may be anesthetized withmethoxyflurane. A small abdominal incision is then made, and the pylorusligated. Immediately after the ligation, a solution of the test compoundor vehicle (distilled water) is injected into the proximal duodenum. Thedoses of test compound used should be 0.01-20 mg/kg body weight. Theincisions are then closed and the rats allowed to recover from theanesthesia. Two hours after the ligation, the rats are sacrificed andthe gastric fluid collected and cleared by centrifugation. Total volumeof secretion is determined by weight, and acidity is determined bytitration to pH 7.0 with 0.1 N sodium hydroxide using an automatictitrator. The data from two experiments are then pooled. A group of ratstreated with 10 mg/kg of of the anti-secretory histamine H₂-receptorantagonist cimetidine may be included as a positive control. Statisticalevaluations can be made using Student's t-test.

[0588] In vitro activity for relaxation of contracted ileum fromisolated guinea pig ileum is determined according to the followingprocedures. Fresh, isolated segments of guinea pig ileum (about 1.5 cmin length) are mounted in tissue baths containing Tyrode's physiologicalsalt solution at about 30° C. and aerated continuously withoxygen:carbon dioxide (95%:5%). Tissues are then equilibrated for 60-90minutes under 4.0 gm tension in order to achieve stable baselines.Histamine is then added to the baths and in a cumulative fashion inconcentrations ranging from 1 nM to 10 mM. The maximum tension generatedafter each addition of histamine is recorded on a Grass Physiograph(Grass Medical Instruments, Quincy, Mass.). The tissues are then washedwith several changes of Tyrode's solution, basal tension is readjustedto 4.0 gm, and a stable baseline is then again obtained. Each tissue isthen exposed to a single concentration of a test compound (1nM-10 mM) orvehicle and, after a thirty minute equilibration period, the histaminedose response curve is then repeated. Results from multiple experimentsare standardized (0-100%) to the maximum response of the control tissuesand plotted as percent maximum tension vs. the log of the histamineconcentration in the absence and presence of the test compound.

Assay 7

[0589] Protection Against Gastric Ulceration

[0590] Food (but not water) is withheld from female Sprague-Dawley rats(Charles River, Wilmington, Mass.) weighing 70-120 g. Access is thenpermitted to food for ninety minutes. A single dose of test compound isthen administered p.o. (0.01-20 mg/kg in a dosing volume of 1 ml/100 g),and indomethacin (Sigma Chemical Co., St. Louis, Mo.) (60 mg/kg, 1ml/100 g body weight) is then injected subcutaneously. Control ratsreceive the subcutaneous injection of indomethacin and oraladministration of vehicle (0.5% methyl cellulose in distilled water) forthe β-adrenoceptor agonist. The animals are then allowed continuedaccess to food but water is withdrawn. The animals are then sacrificedby cervical dislocation six hours after dosing with indomethacin. Thestomach are then removed, opened along the greater curvature and washedin 0.9% saline. An assessment of gastric damage is carried out by anobserver who is unaware of the dosing regimen. A transparent plasticgrid divided into 1 mm² sections is placed over the antrum and the areaof macroscopic damage assessed as the total area of visible lesions inmm². This value is then expressed as a percentage of the total antralarea.

Assay 8

[0591] Anti-Depressant Activity

[0592] Male CD1 mice weighing between 20 and 25 g, and Sprague-Dawleyrats weighing between 200 and 250 g are obtained from Charles River,Wilmington, Mass. Test compounds of Formula (I) are dissolved in water.The compounds are administered to mice in a volume of 10 ml/kg, and torats in a volume of 2 ml/kg. Control animals receive the vehicle.Positive test results for the following parameters indicateanti-depressant activity.

[0593] (1) Antagonism of Hypothermia Induced by Reserpine

[0594] Mice are administered reserpine (2.5 mg/kg i.p. dissolved in 1%citric acid). Their rectal temperatures are measured three and one-halfhours later. The mice are then divided into different groups so as toobtain the same mean rectal temperature in each group. One-half hourlater, (i.e., four hours after reserpine administration), the mice aregiven the vehicle or test compound. Rectal temperature is measured againninety minutes later (i.e., five hours and thirty minutes afterreserpine administration) (Bourin, et al., The Value of the ReserpineTest in Psychopharmacology, Arzneim. Forsch., 33, 1173, (1983)).

[0595] (2) Antagonism of Hypothermia Induced by Apomorphine

[0596] One-half hour after the mice are placed in individual cages,their rectal temperatures are recorded. The animals are allocated so asto obtain the same mean rectal temperature in each group. Apomorphine(16 mg/kg s.c.) is given thirty minutes after the test compound orvehicle. Rectal temperature is then measured again thirty minutes afterthe apomorphine treatment (Puech, et al., Antagonism of Hypothermia andBehavioral Response to Apomorphine; A Simple, Rapid, and DiscriminatingTest for Screening Anti-Depressants and Neuroleptics,Psychopharmacology, 75, 84, (1981)).

[0597] (3) Effect on Learned Helplessness Behavior

[0598] This test is performed essentially as described by Giral, et al.,Reversal of Helpless Behavior in Rats by Putative 5-HT_(1A) Agonists,Biol. Psychiat., 23, 237 (1988). Electric footshocks are delivered tomale albino Sprague-Dawley rats placed in chambers (20×10×10) withPlexiglass® walls and covers. The floors are made of stainless-steelgrids (1.5 cm mesh). A constant-current shock is delivered as sixtyscrambled, randomized inescapable shocks (15 sec. duration, 0.8 mA,every 60+15 sec.) to the grid floor. Control rats are then placed inidentical chambers, but no shock is administered. All preconditioningtrials are performed on Day 1 between 9 and 11 a.m. Avoidance trainingis initiated 48 h (Day 3) after inescapable shock in automated two-wayshuttle boxes (60×21×30 cm) with Plexiglass® walls and a floorconsisting of stainless-steel rods spaced 1.0 cm apart in order toevaluate escape deficits. Each shuttle box is divided into two chambersof equal size by a stainless-steel partition with a gate providingaccess to the adjacent compartment through a 7×7 cm space. Shuttle boxsessions are performed for three consecutive days (Days 3, 4, and 5).The animals are placed individually in the shuttle box and allowed tohabituate to the environment for five minutes (for the first sessiononly) and then subjected to thirty trials. The intertrial intervalshould be thirty seconds. A light signal, used as a conditionedstimulus, is presented during the first three seconds of each trial.Crossing the gate into the other compartment of the box during this“conditioned stimulus only” period (referred to as avoidance response)allows rats to avoid shocks. A period with conditioned stimulus plusfoot-shock (0.8 mA) may be presented if an avoidance response does notoccur. Crossing the gate into the other compartment during thisconditioned stimulus plus shock period is referred to as an escaperesponse. Absence of escape response during the three-second durationconditioned stimulus plus shock is considered to be an escape failure.

[0599] The rats (n=10 per group) are treated randomly according to oneof the following protocols: the control sample, which receives no shock,and is given only vehicle, or experimental animals with inescapableshock are treated daily with vehicle or test compound. Animals aretreated orally over five consecutive days, i.e. six hours after shockpretreatment on Day 1, and then twice per day, a half dose in themorning (30 minutes before shuttle box session) and half a dose in theafternoon (except on day 5). Statistical analysis is performed on themean number of escape failures using a two-way analysis of variance(subjects x sessions) followed by Dunneft's test.

Assay 9

[0600] Bronchial Relaxation and Ciliary Motility

[0601] In vitro activity of the compounds of Formula (I) for thetreatment of airway inflammatory disorders, such as asthma andobstructive lung disease, may be determined by measurement of guinea pigbronchial ring relaxation according to the following procedure.

[0602] Guniea pig bronchial rings are obtained from tricolored guineapigs of either sex (250-350 g), anesthized with urethane (1.25 g/kg) andsuspended under an initial tension of 2.0 g in Krebs solution at 37° C.gassed with 95% oxygen:5% carbon dioxide. After about one hour ofequilibration, the guinea pig bronchial rings are contracted withacetylcholine (10-3 M), relaxed to maximal relaxation with theophylline(10-3 M), and then allowed to equilibrate for a further sixty minuteswhile they are washed with Krebs solution every fifteen minutes.

[0603] Changes in tension are measured isometrically with strain guagesand amplifiers and displayed on a recorder. The composition of the Krebssolution is (mM):NaCl 118.0, FCI 5.4, CaCl₂, 2.5, KHPO₄ 1.2, MgSO₄ 1.2,NaHCO₃ 25.0, and glucose 11.7.

[0604] To test effects of test compounds on resting tension, cumulativeconcentration-response curves are obtained by addition of the testcompounds (10⁻⁹-10⁻⁶ M) every ten to twenty minutes until a plateau isreached. The relaxant effects of the test compounds are expresed aspercentages of the maximal relaxations induced by theophylline (3×10⁻³M).

Assay 10

[0605] Prostate Disease

[0606] Ventral prostates of male Sprague-Dawley rats (300-400 g)anesthetized with diethyl ether are quickly excised and placed inoxygenated Krebs solution. While maintained at room temperature in thisbuffer, adherent fatty and connective tissues are removed. The prostatesare then suspended in 10 ml organ baths containing Krebs solution warmedto 37° C. and aerated with a mixture of 95% oxygen and 5% carbondioxide. The composition of the Krebs solution is 118.4 mM NaCl, 4.7 mMKCI, 1.2 mM MgSO₄, 2.5 mM CaCl₂, 11.1 mM dextrose, 25.0 mM NaHCO₃ and1.2 mM KH₂PO₄, dissolved in distilled and demineralized water. Thetissues are attached to isometric force-displacement transducers andisometric contraction is recorded under a loading tension of 0.5g.Equilibration is undertaken for one or two hours before the addition oftest compounds. Submaximal contractions are first elicited by repeatedconcentrations of 1×10⁻⁶M phenylephrine until constant responses areobtained. The control and test compound-treated experiments areperformed in different preparations. A concentration-response curve tocumulate concentrations of phenylephrine or acetylcholine (10⁻⁹ to10⁻⁴M) is determined. For testing compounds, a concentration responsecurve to phenylephrine or acetylcholine is determined in the presence ofthe compounds.

[0607] In vitro activity of compounds of Formula (I) can also bedetermined for specific efficacy in human prostate as follows.

[0608] Prostatic tissue specimens are obtained from patients withsymptomatic BPH, who are undergoing open prostatectomy. Isolated humanprostatic tissue is cut into five to eight strips (3 mm wide, 3 mm thickand 15 mm long in each strip). The strips are mounted vertically inorgan baths containing 20 ml Krebs-Henseleit solution of the followingcomposition (mM): NaCl 112, KCI 5.9, MgCl₂ 1.2, CaCl₂ 2, NaHCO₃ 25,NaHPO₄ 1.2, glucose 11.5. The medium is maintained at 37° C. and at pH7.4, and is equilibrated with a gas mixture consisting of 95% oxygen and5% carbon dioxide. A resting tension of 0.5 g is applied and theresponses are recorded isometrically through a force-displacementtransducer. The preparations are equilibrated for ninety minutes beforestarting the experiments.

[0609] Concentration-response curves for phenylephrine or acetylcholine(10⁻⁹ to 10⁻⁴M) are determined by adding the compound directly to thebathing media in a cumulative fashion. For testing compounds, theprostate strips are incubated in the presence of compound (1 or 10 μM)for thirty minutes before and then phenylephrine or acetylcholine areadded to the medium in a cumulative fashion to obtain to theconcentration-response curve in the presence of the compound.

Assay 11

[0610] Effect on Triglyceride Levels and Dyslipidemia

[0611] Compounds of the Formula (I) lower triglyceride levels andcholesterol levels and raise high density lipoprotein levels and aretherefore of use in combating medical conditions wherein such lowering(and raising) is thought to be beneficial. Thus, the compounds ofFormula (I) can be used in the treatment of hypertriglyceridaemia,hypercholesterolemia, and conditions of low HDL (high densitylipoprotein) levels in addition to the treatment of atheroscleroticdisease such as of coronary, cerebrovascular and peripheral arteries,cardiovascular disease and related conditions.

[0612] Activity of compounds of Formula (I) for dyslipidemia can bedetermined according to the following procedure. C57BL/6J ob/ob mice(male, 30-40 g body weight, Jackson Lab, Bar Harbor, Me.), housed 5 miceper cage in an environmentally controlled room, are dosed once or twicedaily for three weeks with test compound (0.01-20 mg/kg, n=15 per group)or vehicle (0.5% wlv methyl cellulose/distilled water, water, or othersuitable vehicle) by oral gavage. At the end of the study, twenty-fourhours after giving the final dose of compound, the mice are sacrificedby decapitation and blood collected. Plasma concentrations of free fattyacids and triglyceride are determined using a clinical autoanalyzer(Abbott Spectrum® CCx; Abbott Laboratories, Abbott Park, Ill.).

Assay 12

[0613] Decrease in Body Fat

[0614] Activity of compounds of Formula (I) for decrease in body fat canbe determined according to the following procedure. C57BL/6J ob/ob mice(male, 30-40 g body weight, Jackson Lab, Bar Harbor, Me.) are housedfive mice per cage in an environmentally controlled room with food(pelleted rodent chow) and water available ad libitum. The compound orvehicle (0.5% w/v methyl cellulose/distilled water, water, or othersuitable vehicle) is dosed once or twice daily for three weeks (0.01-20mg/kg, n=15 per group) by oral gavage. Body weight of each mouse ismeasured daily and food intake per cage determined by weighing theamount of food left in the trough. At the end of the study, twenty-fourhours after giving the final dose of compound, the mice are weighed andthen sacrificed by cervical dislocation. The epididymal fat pads fromeach mouse are excised and weighed. The fat versus body weight ratio isdetermined for each mouse using the absolute body weights and the fatpad weights. A reduction in fat pad weight is indicative of a reductionin total body fat.

1. A compound of Formula (I)

the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of said compounds, stereoisomers and prodrugs, wherein:Ar is pyridyl, oxazolyl, thiazolyl, or phenyl; R is hydrogen, hydroxy,oxo, halogen, —CF₃, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl,—NR₉R₁₀, —NR₉SO₂R₁₀, —NR₉COR₁₀, or —SO₂R₉; R₁ is hydrogen,—(C₁-C₆)alkyl, halogen, —(C₁-C₆)alkoxy, or hydroxy; R₂, R₃, R₄ are,independently, hydrogen, or —(C₁-C₆)alkyl; R₅ is a 5- or 6-membered ringheterocycle having from 1 to 4 heteroatoms selected from the groupconsisting of oxygen, sulfur, or nitrogen; R₆ and R₇ are, independently,hydrogen, halogen, cyano, oxo, —(C₁-C₆)acyl, —CO₂R₉, —NR₉R₁₀, hydroxy,—(C₁-C₆)alkoxy, —CONR₉R₁₀, —NR₉SO₂R₁₀, -SO₂NR₉R₁₀, or —SO₂R₉;—(C₁-C₆)alkyl, optionally substituted with —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; —(C₃-C₈)cycloalkyl,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, -SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; aryl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; or heterocycle,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; R₈ is hydrogen,—(C₁-C₄)alkyl, or halogen; and R₉ and R₁₀ are, independently, hydrogen,—(C₁-C₆)alkyl, alkylalkoxy, —(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl,—(C₁-C₆)alkoxy, aryl, or heterocycle; X is a direct bond or oxygen; andY is a direct bond, —(C₁-C₆)alkyl, —OCH₂—, —CH₂O—, or oxygen; providedthat: (i) when Ar is phenyl, R is —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; and(ii) when Ar is phenyl, —NR₉SO₂R₁₀, and R₆ and R₇ are both hydrogen,then R₅ is not imidazolyl.
 2. A compound according to claim 1, whereinAr is pyridyl; R, R₁, R₂, R₃, R₄, and R₈ are hydrogen; X is oxygen; Y isa direct bond; and R₅ is a five- or six-membered ring heterocycleselected from the group consisting of dihydropyridazinonyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl,pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, andtriazolyl.
 3. A compound according to claim 2 selected from the groupconsisting of:(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl]-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-ethyl-oxazol4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;(R)- 2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl)-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxyl-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino-ethanol;(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;and(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol4-yl)-phenoxy]-ethylamino}-ethanol;a stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof said compound, stereoisomer, or prodrug.
 4. A compound according toclaim 3 selected from the group consisting of:(R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;and(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;a stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof said compound, stereoisomer, or prodrug.
 5. A compound according toclaim 1 wherein Ar is phenyl; R is —NR₉SO₂R₁₀; R₁ is hydrogen, hydroxy,or halogen; R₂, R₃, R₄, and R₈ are hydrogen; X is oxygen; Y is a directbond; and R₅ is a five- or six-membered ring heterocycle selected fromthe group consisting of dihydropyridazinonyl, imidazolyl, isothiazolyl,isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl,thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.
 6. Acompound according to claim 5 selected from the group consisting of:(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino}-ethyl}-phenyl)-methanesulfonamide;and(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;a stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof said compound, stereoisomer, or prodrug.
 7. A compound according toclaim 6 selected from the group consisting of:(R)-N-[2-chloro-5-(2-{4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(2-{4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-(4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;(R)-N-(2-chloro-5-{l-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl)-phenyl)-methanesulfonamide;(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;and(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-sulfonamide;a stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof said compound, stereoisomer, or prodrug.
 8. A method of treating a β₃adrenergic receptor-mediated disease, condition, or disorder in a mammalin need of such treatment which method comprises administering to saidmammal a therapeutically effective amount of a compound of claim 1, astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof said compound, stereoisomer, or prodrug.
 9. A method according toclaim 8 wherein said β₃ adrenergic receptor-mediated disease, condition,or disorder is selected from the group consisting of obesity, diabetes,irritable bowel syndrome, inflammatory bowel disease, esophagitis,duodenitis, Crohn's Disease, proctitis, asthma, intestinal motilitydisorder, ulcer, gastritis, hypercholesterolemia, cardiovasculardisease, urinary incontinence, depression, prostate disease,dyslipidemia, and airway inflammatory disorder.
 10. A method ofincreasing lean meat content in an edible animal which method comprisesadministering to said edible animal a lean meat increasing amount of acompound of claim 1, a stereoisomer, or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug.
 11. A pharmaceutical composition which comprises a compound ofclaim 1, a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of said compound, stereoisomer, or prodrug, and apharmaceutically acceptable carrier, vehicle, or diluent.
 12. A methodof treating a β₃ adrenergic receptor-mediated disease, condition, ordisorder in a mammal in need of such treatment which method comprisesadministering to said mammal a therapeutically amount of a compositionof claim
 11. 13. A method according to claim 12 wherein said β₃adrenergic receptor-mediated disease, condition, or disorder is selectedfrom the group consisting of obesity, diabetes, irritable bowelsyndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn'sDisease, proctitis, asthma, intestinal motility disorder, ulcer,gastritis, hypercholesterolemia, cardiovascular disease, urinaryincontinence, depression, prostate disease, dyslipidemia, and airwayinflammatory disorder.
 14. A method of increasing lean meat content inan edible animal which method comprises administering to said edibleanimal a lean meat increasing amount of a pharmaceutical composition ofclaim
 11. 15. A pharmaceutical composition which comprises a compound ofclaim 1, a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of said compound, stereoisomer, or prodrug; ananti-obesity agent; and a pharmaceutically acceptable carrier, vehicle,or diluent.
 16. A composition according to claim 15 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, an MCR4 agonist, a CCK-A agonist, a monoamine reuptakeinhibitor, a sympathomimetic agent, a serotoninergic agent, a dopamineagonist, a melanocyte-stimulating hormone receptor analog, a cannabinoidreceptor antagonist, a melanin concentrating hormone antagonist, leptin,a leptin analog, a leptin receptor agonist, a galanin antagonist, alipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, athyromimetic agent, dehydroepiandrosterone or an analog thereof, aglucocorticoid receptor agonist or antagonist, an orexin receptorantagonist, a urocortin binding protein antagonist, a glucagon-likepeptide-1 receptor agonist, and a ciliary neurotrophic factor, or AGRP.17. A composition according to claim 16 wherein said anti-obesity agentis selected from the group consisting of phentermine, ephedrine, leptin,phenylpropanolamine, and pseudoephedrine; said monoamine reuptakeinhibitor is sibutramine; said serotoninergic agent is fenfluramine ordexfenfluramine; said dopamine agonist is bromocriptine; said lipaseinhibitor is orlistat; and said anorectic agent is a bombesin agonist.18. A method of treating β₃ adrenergic receptor-mediated disease,condition, or disorder in a mammal in need of such treatment whichmethod comprises administering to said mammal a therapeuticallyeffective amount of a composition of claim
 15. 19. A method according toclaim 18 wherein said β₃ adrenergic receptor-mediated disease,condition, or disorder is selected from the group consisting of obesity,diabetes, irritable bowel syndrome, inflammatory bowel disease,esophagitis, duodenitis, Crohn's Disease, proctitis, asthma, intestinalmotility disorder, ulcer, gastritis, hypercholesterolemia,cardiovascular disease, urinary incontinence, depression, prostatedisease, dyslipidemia, and airway inflammatory disorder.
 21. A method ofincreasing lean meat content in an edible animal which method comprisesadministering to said edible animal a lean meat increasing amount of apharmaceutical composition of claim
 15. 22. A compound of the formula

or an acid addition salt thereof, wherein: R₅ is a 5- or 6-membered ringheterocycle selected from the group consisting of isothiazolyl,isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazolyl, pyridazinyl,thiadiazolyl, thiazolinyl, thiazolyl, and triazinyl; R₆ and R₇ are,independently, hydrogen, halogen, cyano, oxo, —(C₁-C₆)acyl, —CO₂R₉,—NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, -CONR₉R₉, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or—SO₂R₉; —(C₁-C₆)alkyl, optionally substituted with —(C₃-C₈)cycloalkyl,halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy,—NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;—(C₃-C₈)cydoalkyl, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; aryl, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₃-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; or heterocycle, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and Y is adirect bond, or —CH₂—.
 23. A compound according to claim 22 selectedfrom the group consisting of:2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamine;2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamine;2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamine;2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamine;2-[4-(4-ethyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamine;2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamine;2-(3-methyl-4-oxazol-4-yl)-phenoxy]-ethylamine;2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamine;2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine;2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamine;2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamine;2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamine;2-(4-[1,3,5]oxadiazol-2-yl-phenoxy)-ethylamine;2-(4-oxazol-2-yl-phenoxy)-ethylamine;2-(4-oxazol-4-yl-phenoxy)-ethylamine;2-(4-oxazol-5-yl-phenoxy)-ethylamine;2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine;2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine;2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamine;2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamine;2-(4-pyrazol-1-yl-phenoxy)-ethylamine;2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamine;2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamine;2-4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamine;2-(4-[1,2,3]thiadiazol-5-yl-phenoxy)-ethylamine;2-(4-thiazol-2-yl-phenoxy)-ethylamine;2-(4-thiazol-4-yl-phenoxy)-ethylamine;2-[4-(2-thiophen-2-ylthiazol-4-yl)-phenoxy]-ethylamine;2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamine;2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamine;2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamine;2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamine; and2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamine; or an acidaddition salt thereof.